Carbon-11: Radiochemistry and Target-Based PET Molecular Imaging Applications in Oncology, Cardiology, and Neurology
- Nerella Sridhar Goud*Nerella Sridhar Goud*Email: [email protected]Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, IndiaMore by Nerella Sridhar Goud,
- Ahana BhattacharyaAhana BhattacharyaDepartment of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, IndiaMore by Ahana Bhattacharya,
- Raman Kumar JoshiRaman Kumar JoshiDepartment of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, IndiaMore by Raman Kumar Joshi,
- Chandana NagarajChandana NagarajDepartment of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, IndiaMore by Chandana Nagaraj,
- Rose Dawn BharathRose Dawn BharathDepartment of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, IndiaMore by Rose Dawn Bharath, and
- Pardeep KumarPardeep KumarDepartment of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, IndiaMore by Pardeep Kumar
Copyright © 2021 American Chemical Society
Abstract
The positron emission tomography (PET) molecular imaging technique has gained its universal value as a remarkable tool for medical diagnosis and biomedical research. Carbon-11 is one of the promising radiotracers that can report target-specific information related to its pharmacology and physiology to understand the disease status. Currently, many of the available carbon-11 (t1/2 = 20.4 min) PET radiotracers are heterocyclic derivatives that have been synthesized using carbon-11 inserted different functional groups obtained from primary and secondary carbon-11 precursors. A spectrum of carbon-11 PET radiotracers has been developed against many of the upregulated and emerging targets for the diagnosis, prognosis, prediction, and therapy in the fields of oncology, cardiology, and neurology. This review focuses on the carbon-11 radiochemistry and various target-specific PET molecular imaging agents used in tumor, heart, brain, and neuroinflammatory disease imaging along with its associated pathology.
1. Introduction
ARTICLE SECTIONS
Positron emission tomography (PET) is regarded as an important molecular imaging modality to study the pathophysiological conditions in animals (preclinical studies), human subjects (clinical studies), and drug development (drug discovery).(1,2) The PET modality plays a wide role in medical diagnosis, mainly in tumors, the heart, and the nervous system. The major advantage of PET is to measure the very low concentration (10–6–10–9 g) of radiotracers at a specific region of interest in a living subject, either animal or human, or throughout a whole body.(3,4) In general, positron-emitting radiotracers like fluorine-18 and carbon-11 are injected intravenously into a specific region of interest, and the tracers generate two γ-rays with 511 keV energy in almost opposite directions after annihilating with an electron in the living subjects.(5) The high-resolution images are obtained from PET detectors based on the distribution of the positron-emitter after reconstruction of coincident arrivals of the γ-rays.(6) The essential steps which are followed in the process of PET imaging include the production of radionuclide, radiolabeling studies with a precursor, imaging, and quantitative analysis.
The limited anatomic data provided by PET scanners is the main drawback. However, this limitation has been largely overcome by multimodality devices like PET-CT, SPECT-CT, and, most recently, PET-MRI. PET scanners are routinely combined with CT and MRI for attenuation correction and anatomical orientation. PET has a high spectral resolution (2–6 mm) [it is higher than that of CT and MRI (≪1 mm)], and the sensitivity of PET (10–12 M) is much greater than the MRI modality (10–4 M). Therefore, PET remains an invaluable molecular imaging modality, even through the combination of PET-CT or PET-MR in biomedical and clinical practice.(7,8)
The imaging output from PET gives clear information related to the distribution of radioactivity and pharmacokinetics which in turn depend on the chemical nature of the radiotracer and the physiological conditions of the living subjects. Thus, the design of a specific radiotracer is an essential step for target selectivity and its distribution in the region of interest. For instance, few of the designed radiotracers are utilized for various purposes; i.e., [18F]FDG (18F-2-fluoro-2-deoxy-d-glucose) (1) shows a report on glucose metabolism which is normal in healthy subjects but shows the high rate in different pathophysiological conditions, such as tumors and various neurological disorders,(9) and [18F]FLT (18F-3′-fluoro-3′-deoxythymidine) (2) is a thymidine kinase-1-based substrate and widely used for the study of cell growth in tumors (Figure 1).(10)[11C]Flumazenil (3) is considered as a ligand for brain GABAA benzodiazepine receptors to study the condition of epilepsy.(11)[11C]Raclopride (4) is a specific D2 and D3 receptor antagonist widely used for the diagnosis of Parkinson’s disease.(12)[11C]Methionine (5) is an aliphatic amino acid involved in amino acid transport and protein incorporation and is widely used in the diagnosis of multiple cancer types.(13)[11C]Choline (6) is the precursor to acetylcholine neurotransmitter synthesis, the activity of which is impaired in a majority of neurodegenerative diseases, and also used in the diagnosis of prostate cancer.(14) The modern computational modeling studies like ligand-based and structure-based drug design and structural–activity relationship studies help identify target-specific drugs.(15)
Figure 1
Figure 1. Commonly used PET radiotracers for diagnosis under various clinical conditions.
1.1. Carbon-11 Radiochemistry
Carbon-11 (t1/2 = 20.4 min, β+ emission = 99.8%) is the most useful short-lived positron-emitting radiotracer for developing PET molecular images. The cyclotron generated carbon-11 radionuclide replaces a stable carbon-12 atom in the desired organic molecule to produce target-based carbon-11 radiotracers.(16) In general, the medical cyclotron generates carbon-11 radionuclide in two different sources, either [11C]carbon dioxide or [11C]methane, using different target material composition through the 14N(p,α)11C nuclear reaction (Figure 2). The [11C]carbon dioxide is produced from nitrogen with oxygen ∼0.1–1% target in high activities around ∼118 GBq with an energy utilization of 11–17 MeV, whereas the [11C]methane is produced from nitrogen with hydrogen ∼10% target in normal activities around ∼67 GBq with an energy utilization of 18 MeV.(17) The [11C]methane production was also reported from cyclotron-produced [11C]carbon dioxide by online reduction with hydrogen and nickel at around 580 °C.(18) The carbon-11 radionuclide undergoes a β+-decay process by losing a positron and an electron neutrino into a stable boron-11 isotope. The method of carbon-11 production is known as the no-carrier-added (NCA) method, which means the theoretical specific (GBq/mg) or molar activity (GBq/μmol) (absence of other than the specified isotope) should be attained. This method is different from the carrier-added (CA) method in which molecular 18F-fluorine (18F–F) is produced, where the theoretical specific (GBq/mg) or molar activity (GBq/μmol) (presence of other including the specified isotope) is not attained. Therefore, the ratio of radioactive to non-radioactive species in NCA (higher molar activities) is always greater than CA (lower molar activities).(19) The PET studies usually need to be NCA for targeting low-density proteins like neurotransmitter receptors, transporters, or plaque to avoid the target protein saturation point with the carrier (non-radioactive molecule) and to reduce the target-based PET signal.(20) Molar activities always depend on time and decay of the radioisotope. Hence, the molar activity values pertaining to a specific time, such as time of radiotracer injection into a PET study subject (TOI), end of radiosynthesis (EOS), and end of radionuclide production (ERP), are also referred to as the end of bombardment (EOB).(21)
Figure 2
Figure 2. Cyclotron production and β+-decay process of carbon-11 radionuclide.
The PET studies in human subjects require about 15 mCi or 550 MBq of carbon-11 radiotracer at the TOI after passing all necessary quality control tests, whereas the PET studies in animal subjects require lower radioactive doses and are based on animal size.(22) Dynamic PET imaging studies require higher NCA molar activities than static PET imaging studies. The majority of PET studies are performed with a NCA radiotracer molar activity value >35 GBq/μmol in human subjects. As the half-life of carbon-11 is 20 min, each step needs to be performed very rapidly, including radiochemical synthesis, purification, final formulation, and dispensing for intravenous injection to a living subject. High-performance liquid chromatography (HPLC) provides the carbon-11 radiotracer purification through specific preparative methods and also determines the radiochemical purity, radiochemical identity, radiochemical yields, and molar activity concentration through analytical methods using suitable chromatographic conditions.(23) Thin-layer chromatography (TLC) provides retardation factor (Rf) values for the carbon-11 radiotracer based on its affinity toward the mobile phase on the silica gel stationary phase and determines the radiochemical purity and radiochemical yield.(24) The gas chromatography (GC) provides residual solvent limits of the final formulation after the radiochemical synthesis in ppm units.(25) The bacterial endotoxin test with limulus amebocyte lysate (LAL) reagent should be passed before injecting into a living subject.(26)
Fluorine-18 mainly follows two methods majorly for radiolabeling like electrophilic radiofluorination and nucleophilic radiofluorination, whereas the carbon-11 follows versatile routes by generating primary and secondary precursors. [11C]Carbonylation is one of the most common approaches for inserting carbon-11 into various drug molecules. The investigation of new carbon-11-based radiosynthesis with direct radioactive materials rather than optimization trials with unlabeled material, unlike fluorine-18, is the major advantage of carbon-11. Carbon-11-based synthons can be generated for opening additional routes for carbon-11 radiolabeling in various selective molecules. The short half-life of carbon-11 is the major limitation, and the proximity of the radiochemist is required to speed up the process.(27,28)
1.2. Carbon-11 Precursors for Radiolabeling
The carbon-11 precursors are classified into primary and secondary based on their utility and wide range of applications in the radiolabeling of various compounds like aliphatic, aromatic, and heterocyclic compounds after the production of carbon-11 radionuclide (Figure 3). It is known that the carbon-11 is generated from cyclotron using the 14N(p,α)11C nuclear reaction through the collision of nitrogen gas with a trace amount of either hydrogen or oxygen. Besides, the nitrogen-13 is also produced in trace amount as an impurity via 16O(p,α)13N nuclear reaction. In practice, the yields of carbon-11 are very high due to a high nitrogen concentration and low oxygen (<1%) levels in the target gas.(29)
Figure 3
Figure 3. Transformation of different precursors from carbon-11 radionuclide.
1.2.1. Primary Carbon-11 Precursors
The carbon-11 in the chemical form of [11C]CO2 and [11C]CH4 is considered as the primary carbon-11 precursors, which can be produced during in-target production. Other primary precursors like [11C]CO and NH4[11C]CN can be generated in the target by changing the l of hydrogen and oxygen along with beam current, but the respective yields are very poor. Even the approaches of developing [11C]CH3I as primary precursors are under scientific validation.(29) The [11C]carbon dioxide has direct utility in the labeling of some compounds, mainly in direct [11C]carboxylation reactions with organometallic reagents, and reactions with amines, etc. The previous reports suggest the direct incorporation of [11C]carbon dioxide (11C–CO2 fixation) into functional groups such as urea ([11C]AR-AO14418, selective GSK-3β inhibitor) (7), carbamate ([11C]GR103545, kappa opioid agonist) (8), oxazolidinone ([11C]SL25.1188, monoamine oxidase-B inhibitor) (9), carboxylic acid ([11C]bexarotene, retinoid X receptor (RXR) agonist) (10), amide (11C-WAY-100635, 5-HT1A receptor agonist) (11), and amine ([11C]PHNO, dopamine D2 and D3 receptor agonist) (12) for the synthesis of various carbon-11 radiotracers (Figure 4).(30−33)
Figure 4
Figure 4. Reaction pathways for [11C]CO2 fixation into urea, carbamates, oxazolidinones, carboxylic acids, amides, and their carbon-11 radiotracer derivatives.
1.2.2. Secondary Carbon-11 Precursors
The primary carbon-11 precursors like [11C]CO2 and [11C]CH4 are converted into secondary precursors by rapid and efficient online or one-pot synthetic procedures to produce building blockers for generating carbon-11 radiotracers. There are several useful transformations for the generation of secondary precursors. Many of the potential radiotracers are generated using various secondary precursors, which include [11C]flumazenil (GABAA benzodiazepine receptors) (3) from 11CH3I precursor, [11C]raclopride (cerebral D2/D3 receptor antagonist) (4) from 11CO precursor, 11C(carbonyl)-estramustine phosphate (estrogen receptor agonist) (13) from 11COCl precursor, [11C]thymidine (pyrimidine derivative for DNA synthesis) (14) from 11COCl2 precursor, [11C]citalopram (selective serotonin reuptake inhibitor) (15) from 11CN precursor, [11C]serine (synaptic N-methyl-d-aspartate receptors) (16) from 11CH2O precursor, [11C]tanaproget (selective progesterone receptor modulator) (17) from 11CS2 precursor, and [11C]NS14492 (α7-subtype nicotinic Ach receptor agonist) (18) from 11CH3OTf precursor (Figure 5).
Figure 5
Figure 5. Reaction pathways for generation of secondary precursors and their carbon-11 radiotracer derivatives.
1.2.2.1. Transformations of Secondary Precursors from [11C]CO2
The 11C-carbon monoxide is an important and widely used secondary labeling agent, which is prepared by reducing [11C]carbon dioxide over heat at 400 °C with zinc or heating at 850 °C with molybdenum. The synthesis of [11C]carbon monoxide was also reported from in situ generated 11C-formate or [11C]formyl chloride from 11C-carbon dioxide with lithium triethylborohydride, hexachloroacetone, and triphenylphosphine; recently, the silyl reagents are used most commonly for generating [11C]carbon monoxide in the liquid phase.(34−36) [11C]Carbon dioxide can also be converted into [11C]formaldehyde by reducing it to [11C]methanol, followed by oxidation over heated silver wool at 350 °C; another method was also reported, i.e., [11C]methyl iodide using trimethylamine N-oxide (TMAO) at 70 °C.(37) [11C]Acyl chloride or aryl acid chloride can be synthesized from [11C]carbon dioxide using an appropriate Grignard reagent followed by subsequent chlorination using either thionyl chloride or phthaloyl dichloride.(38,39) [11C]Methyl iodide is another commonly used secondary agent. A common method of generating [11C]methyl iodide is the reduction of [11C]carbon dioxide with lithium aluminum hydride (LAH) followed by subsequent iodination by hydroiodic acid treatment; another method has been reported through gas-phase iodination of [11C]methane for [11C]methyl iodide synthesis.(40,41) [11C]Nitromethane is synthesized from [11C]methyl iodide by passing over heated silver nitrite at 80 °C,(42) and [11C]methyl isocyanate is generated from [11C]methyl iodide by passing over heated silver cyanate at 180 °C.(43) The [11C]methyl triflate is also generated from [11C]methyl iodide by passing over heated silver triflate at 200 °C,(44) and [11C]methyl iodide can be converted into [11C]carbon disulfide by passing over sulfur through a column and sand at 500 °C.(45)
1.2.2.2. Transformations of Secondary Precursors from [11C]CH4
[11C]Hydrogen cyanide can be synthesized from [11C]methane by passing ammonia over heated platinum at 1000 °C.(46) [11C]Methane is transformed into [11C]fluoroform by passing through helium over heated cobalt(III) fluoride at 270 °C.(47) [11C]Phosgene is synthesized from [11C]carbon tetrachloride, which is generated from [11C]methane by passing over copper(II) chloride on pumice stone at 380 °C, followed by a passage with trace oxygen over heated iron at 300 °C or a passage of [11C]carbon tetrachloride over oxygen in a quartz tube at 750 °C.(48,49)
1.3. Carbon-11 Radiolabeling Strategies
The radiochemistry of carbon-11 is challenging because of the shorter t1/2 of carbon-11 which restricts different synthetic methods and time-consuming processes to use. In addition to its normal optimization reaction procedures, three essential steps are needed to be considered to follow an effective strategy for carbon-11-based radio synthesis.(50)
Design reaction protocols to introduce carbon-11 radionuclide at the last step.
In order to achieve good radiochemical yields and molar activity, the reaction time should be reduced.
Reduce isotopic dilution to achieve maximum molar activities.
With the above aspects of effective strategies for carbon-11-based radiosynthesis, various synthetic methodologies and innovations in technology have been adopted. The organic synthetic methods provide great opportunities for the synthesis of various carbon-11 radiotracers by holding carbon chemistry literature. Many carbon-11 tracers are available based on the simplest methylation of heteroatoms with [11C]methyl iodide,(51) but labeling position may not always be possible in different compounds. Therefore, a large number of methodologies have come into the radiochemical synthesis of carbon-11 through the formation of C–C bonds between carbon-11 and labeling molecules.(52) Currently, the following methods are utilized for the synthesis of various 11C-radiotracers through C–C bond formation.
The alkylation of carbanions (nucleophiles) with carbon-11-labeled alkyl halides, nitroalkanes, and cyanide (electrophilic carbon-11).(53)
The carboxylation of organometallic reagents, copper, and other metal-mediated catalysts.(54,55)
Transition-metal-mediated (palladium, rhodium, and selenium) chemical reactions with [11C]CH3I and [11C]CO.(56−59)
Various carbon-11 radiotracers are synthesized through C–C bond formation using different well-known reaction mechanisms like Stille reaction (Pd2(dba)3/11CH3I) for [11C]A85380 (nicotinic Ach receptor agonist) (19), Negishi coupling reaction (Pd(PPh3)2Cl2/11CH3I) for [11C]MPEP (glutamate receptor subtype 5 receptors) (20), Suzuki cross-coupling reaction (Pd(PPh3)2Cl2/11CO) for N-[11C]phenylacetamide derivative (HIV-1 reverse transcriptase inhibitor) (21), Heck reaction (Pd2(dba)3/11CH3I) for [11C]stilbene derivative (targeting amyloid plaques) (22), Sonogashira reaction (Pd2(dba)3/11CH3I) for N-[11C]estradiol derivative (estrogen receptors agonist) (23), and 11C-cyanide cross-coupling reaction (Pd2(dba)3/11CN) for [11C]cyanide derivative (dopamine D3 receptor antagonist) (24) (Figure 6).
Figure 6
Figure 6. Carbon-11 radiotracers through C–C bond formation from various well-known reaction mechanisms.
1.4. Significance of Carbon-11 Labeling in Different Target-Based Heterocycles
The [11C]nicotine (25) as a nicotinic acetyl cholinergic receptor (nAChR) PET imaging agent has been synthesized via two different methods. The first method follows treatment of nornicotine with highly reactive [11C]methyl triflate under mild conditions in acetone at 45 °C for 5 min. The final radiochemical yield obtained was 60.4%. The second method follows treatment of nornicotine with 11C-methyl iodide in the aprotic polar solvents dimethyl sulfoxide–dimethylformamide (DMSO–DMF) at 115 °C for 5 min to study nicotinic receptors with PET, and the radiochemical yield was >90%.(60,61)
The [11C]NS14492 (26) PET radiotracer for imaging human cerebral α7 nicotinic acetylcholine receptors (α7nAChR) has been reported. The radiosynthesis of [11C]NS14492 was achieved by the treatment of its desmethyl precursor with 11CH3OTf in a fully automated system using tetrabutylammonium hydroxide (TBAH) and acetone at 60 °C for 30 min. The achieved radiochemical yield was >98%.(62)
The protein kinase C radiotracer (27) has been synthesized through 11C-methylation of the arylamine precursor with [11C]CH3I at room temperature that was achieved by inorganic base potassium carbonate in dimethylformamide for 10 min with ultrasonication, and the radiochemical yield was 25%. Another method was also developed for the radiochemical synthesis of other arylamines using [11C]CH3I in good yields. The same group has reported the conversion of primary arylamines into carbon-11-labeled N-methyl secondary arylamines using lithium nitride (Li3N) in DMF with [11C]CH3I at room temperature for 10 min with ultrasonication.(63)
The [11C]vemurafenib (28) is a serine/threonine kinase PET imaging agent for the melanomas mainly in the specific expression of the BRAFV600E mutation. The target compound was radiolabeled with [11C]CO through a palladium-catalyzed carbonylative cross-coupling reaction on the arylamine precursor with triphenylarsine and tris(dibenzylideneacetone) palladium (0) [Pd2(dba)3] in tetrahydrofuran (THF) at 100 °C for 5 min. The achieved radiochemical yield was 21%.(64)
The S-[11C]methylated mercaptoimidazole piperazinyl derivatives as PET radiotracers have been reported as 5-HT1A receptor imaging agents. In the radiochemical synthesis, the [11C]methyl group was introduced at the C-2 position of an imidazole ring. Thus, the target radiotracer (29) was synthesized through S-methylation of the imidazole thione precursor with [11C]CH3I using NaOH base in ethanol at 80 °C for 6 min and the radiochemical yield was 20–30%.(65)
The carbon-11-labeled dihydrobenzoimidazol derivative for imaging of NR1A/2B subtype selective N-methyl-d-aspartate (NMDA) receptors has been reported. The synthesis of the target radiotracer (30) was obtained by treatment of the o-aryl diamine precursor with [11C]phosgene and triethylamine (TEA) in dichloromethane solvent at room temperature for <1 min, and the radiochemical yield was 30–50%.(66)
The [11C]oxazolidin-2-one PET radioligand (31) has been developed for imaging monoamine oxidase-B. The precursor ethanolamine derivative was treated with [11C]phosgene in dichloromethane solvent at 100 °C for 2 min, offering the target radiotracer, and the radiochemical yield was 3.5–7%.(67)
The triazole-based monoacylglycerol lipase (MAGL) inhibitors have been reported as PET imaging agents. The triazolyl MAGL radioligand (32) was prepared from the secondary amine precursor through the [11C]carbon dioxide fixation method with BEMP base in phosphoryl chloride at RT for 5–6 min with adequate radiochemical yields of 5–13%.(68)
The [11C]NS14492 (26) PET radiotracer for imaging human cerebral α7 nicotinic acetylcholine receptors (α7nAChR) has been reported. The radiosynthesis of [11C]NS14492 was achieved by the treatment of its desmethyl precursor with 11CH3OTf in a fully automated system using tetrabutylammonium hydroxide (TBAH) and acetone at 60 °C for 30 min. The achieved radiochemical yield was >98%.(62)The protein kinase C radiotracer (27) has been synthesized through 11C-methylation of the arylamine precursor with [11C]CH3I at room temperature that was achieved by inorganic base potassium carbonate in dimethylformamide for 10 min with ultrasonication, and the radiochemical yield was 25%. Another method was also developed for the radiochemical synthesis of other arylamines using [11C]CH3I in good yields. The same group has reported the conversion of primary arylamines into carbon-11-labeled N-methyl secondary arylamines using lithium nitride (Li3N) in DMF with [11C]CH3I at room temperature for 10 min with ultrasonication.(63)The [11C]vemurafenib (28) is a serine/threonine kinase PET imaging agent for the melanomas mainly in the specific expression of the BRAFV600E mutation. The target compound was radiolabeled with [11C]CO through a palladium-catalyzed carbonylative cross-coupling reaction on the arylamine precursor with triphenylarsine and tris(dibenzylideneacetone) palladium (0) [Pd2(dba)3] in tetrahydrofuran (THF) at 100 °C for 5 min. The achieved radiochemical yield was 21%.(64)The S-[11C]methylated mercaptoimidazole piperazinyl derivatives as PET radiotracers have been reported as 5-HT1A receptor imaging agents. In the radiochemical synthesis, the [11C]methyl group was introduced at the C-2 position of an imidazole ring. Thus, the target radiotracer (29) was synthesized through S-methylation of the imidazole thione precursor with [11C]CH3I using NaOH base in ethanol at 80 °C for 6 min and the radiochemical yield was 20–30%.(65)The carbon-11-labeled dihydrobenzoimidazol derivative for imaging of NR1A/2B subtype selective N-methyl-d-aspartate (NMDA) receptors has been reported. The synthesis of the target radiotracer (30) was obtained by treatment of the o-aryl diamine precursor with [11C]phosgene and triethylamine (TEA) in dichloromethane solvent at room temperature for <1 min, and the radiochemical yield was 30–50%.(66)The [11C]oxazolidin-2-one PET radioligand (31) has been developed for imaging monoamine oxidase-B. The precursor ethanolamine derivative was treated with [11C]phosgene in dichloromethane solvent at 100 °C for 2 min, offering the target radiotracer, and the radiochemical yield was 3.5–7%.(67)The triazole-based monoacylglycerol lipase (MAGL) inhibitors have been reported as PET imaging agents. The triazolyl MAGL radioligand (32) was prepared from the secondary amine precursor through the [11C]carbon dioxide fixation method with BEMP base in phosphoryl chloride at RT for 5–6 min with adequate radiochemical yields of 5–13%.(68)2. PET Molecular Imaging Applications in Oncology
ARTICLE SECTIONS
2.1. Receptor Tyrosine Kinases (RTKs)
Tyrosine kinase receptors get abnormally activated during tumor progression and, in turn, contribute toward inadvertent signaling processes of all cancer hallmarks.(69,70) Carbon-11 was labeled with ligand 3-piperidinylethoxyanilinoquinazoline (PAQ), which is an analogue to tyrosine kinase inhibitor (TKI) vandetanib having 40 times higher Ki inhibition against VEGFR-2. [11C]PAQ (33) was used as a PET molecular probe in MMTV-PyMT/FVB (PyMT), a transgenic mouse model of breast cancer, to monitor the anticancer treatment in the animal. The study showed promising results indicating the potential of (R)-[11C]PAQ as a predictive radiotracer in cancer therapy response treatment.(71) The RTKs include an extracellular domain as well as intracellular signaling cascades; these are the targets for various monoclonal-antibody-based small-molecule TKIs, respectively.(72) For the in vivo assessment of pharmacokinetics and biodistribution, TKIs could be radiolabeled with carbon-11. A case report published in 2011 explored the target expression of EGFR and the binding potential of erlotinib using [11C]erlotinib (34) (Tarceva) in a patient with metastases.(73) Other TKI-PET tracers like [11C]lapatinib (35) and [11C]osimertinib (36) were used to study the target expression of HER2 (receptor tyrosine-protein kinase erbB-2) and the brain accessibility and biodistribution in human brain tumors.(74,75)
2.2. Phosphatidylcholine (PC)
Phosphatidylcholine, a phospholipid in eukaryotic cell membranes, is overexpressed in tumor cells, providing a potential target for tumor imaging. Elevated levels of PC are due to the enhanced uptake of choline, which is the precursor of PC.(70−76)[11C]Choline ([11C]CHO) (6) can serve as a potential PET imaging marker for imaging cell proliferation, since it is in proliferating cancer cells. [11C]CHO has been studied in several other types of tumors, including prostate cancer,(77) brain tumors,(78) and many other types of tumors. [11C]CHO is used for the analysis and delineation of HGG, LGG, and extra-axial tumors.(79−81) Its dependency on BBB disruption limits its application as a PET tracer.(82) The Giovacchini group performed a [11C]CHO imaging study in hormone-sensitive prostate cancer patients with low disease burden and excluded patients who showed positive findings for tumor recurrence on clinical imaging. The results of the study reported the potential use of [11C]choline PET/CT for the early restaging of hormone-sensitive prostate cancer cases after radical prostatectomy.(83) In prostate cancer cells, upregulation of choline kinase enzyme occurs, resulting in increased synthesis of PC. [11C]CHO is limited by its incapacity to distinguish tumor uptake from benign prostatic hyperplasia resulting in its limited role in primary disease. Both [11C]CHO and [18F]CHO are commonly used in the detection of biochemically recurrent prostate cancer.(84) The FDA gave its approval for the use of [11C]CHO in the evaluation of biochemically recurrent prostate cancer in September 2012. Several meta-analytical studies with [11C]CHO and [18F]CHO revealed high specificity as well as sensitivity in those patients.(85,86)
The [11C]acetate ([11C]ACE) (40) radiotracer was proposed as a tumor imaging agent in 2003.(87) Acetate is easily activated to acetyl-CoA in the cytosol and mitochondria in the presence of acetyl-CoA synthetase. For the cholesterol and fatty acid synthesis, acetyl-CoA acts as a common metabolite, which is then integrated into the membranes.(88) While in tumor cells, the majority of acetate is rapidly converted into fatty acids by fatty acid synthetase, which is highly expressed in tumors.(89) Initially, [11C]ACE was applied in cardiology and neurology but not in oncology for the measurement of oxidative metabolism in the myocardium and in vivo study of glial–neuronal interactions in the brain.(90,91) [11C]ACE is proved as a PET imaging agent in different tumors like prostate, liver, and others.(92−94) In the cells of prostate cancer, the surplus amount of fatty acid synthase enzyme present is involved in the conversion of acetate to fatty acid (FA) used in the production of PC.(84) [11C]ACE not only helps in the detection of advanced prostate cancer but also helps in the evaluation of localized disease. The Mena group conducted a study on 39 subjects with localized disease and found a higher uptake in tumors compared to the normal prostate tissue.(95) Due to the low sensitivity (75%) and low specificity (76%) of [11C]ACE in the detection of the primary tumor, it cannot be used independently for imaging primary prostate cancer.(96) [11C]ACE PET imaging can be an effective method for the early stage detection of prostate cancer recurrence after radical prostatectomy. Earlier, there were no methods or reference standards to detect tumor growth in the pelvic region. Many groups got positive results representing cancer cell activity in the tumor locations, indicating prostate cancer recurrence, and a correlation between recurrence and SUV value with the initial Gleason score in prostate cancer patients.(97−100) [11C]ACE showed 90% sensitivity in the detection of HGG compared to 100% sensitivity of 11C-MET.(101) [11C]acetate also showed good efficiency in differentiating HGG and LGG(102) and also between grade IV and III gliomas.(103) However, it did not show promising results in tumor grading of meningioma.
2.3. DNA Synthesis
[11C]Thymidine (substrate for TK-1 in DNA synthesis) (37) was synthesized as a PET imaging agent for measurement of the proliferation rate of cells.(104) Proliferative activity of cells is one of the hallmarks of malignant cells. [11C]Thymidine is the first radiotracer to successfully study the proliferative activity in various tumors.(105) The rapid and complex in vivo metabolism of the tracer and the resulting demands on the construction of corresponding input functions made [11C]thymidine unsuitable for routine PET scanning.(106)FMAU (38), a pyrimidine analogue radiolabeled with carbon-11, was shown to be useful for tumor cell proliferation imaging.(107−109) Although [11C]thymidine gets easily incorporated into DNA, it also gets catabolized by thymidine phosphorylase, thus complicating the process of image analysis. 4′-[Methyl-11C]thiothymidine ([11C]4DST) (39), a derivative of thymidine, was developed at the National Institute of Radiological Sciences (NIRS) and was approved for clinical use.(110,111) As [11C]4DST is a nucleoside derivative, it is unable to cross the BBB. Therefore, [11C4DST accumulation in the normal brain is low. The Toyota group carried out a direct comparison of [11C]4DST and [18F]FLT patients with brain tumors. The results indicated that [18F]FLT provided better tumor visualization than [11C]4DST. Also, the results indicated similarity in the uptake pattern and values of both [11C]4DST and [18F]FLT in gliomas.(112) Tanaka et al. performed a retrospective evaluation of 11C-4DST uptake in gliomas and analyzed a correlation between Ki67 and tumor grade against 11C-MET.(113) Further, the uptake value of [11C]4DST and its comparison with [18F]FDG was carried out in several types of cancer, including head and neck cancer,(114) lung cancer,(115) multiple myelomas,(116) and renal cell cancer.(117)
2.4. Amino Acid Transport and Protein Synthesis
2.4.1. Amino Acid Transporters
Depending on the structure, amino acids (AAs) cross cell membranes via amino acid transport systems. In mammals, based on the substrate that is transported, the amino acid transport system can be classified into neutral, acidic, or basic.(118) In tumor cells, to meet the increasing demand of AAs, the expression of amino acid transporters is enhanced. Besides being the building blocks of protein, AAs are the precursors for the synthesis of nucleotides, amino sugars, and glutathione.(119) Thus, amino acid uptake and transport is more important than the rate of protein synthesis in tumor cells.(120) Different transport systems, such as system A, xCT, glutamine, and cationic amino acid transporters, have also been studied in tumor imaging with various radiolabeled amino acid PET tracers.(121−123) Among all of these systems, the l (leucine preferring)-type amino acid transport system is the most suitable transport system for glioma imaging due to its activity at the BBB.(124,125) It has four subtypes—LAT1, LAT2, LAT3, and LAT4. LAT1 is highly expressed in primary human cancers and cancer cell lines due to its importance in the growth and survival of tumor cells. High expression of LAT1 is associated with cell proliferation and angiogenesis, and it is important in cell signaling via the mTOR pathway which is involved in cell growth regulation and division.(126) LAT subtypes 1 and 2 are overexpressed in neoplastic tissues in both gliomas and brain metastases.(127−129) This makes these amino acid transporters a convincing target for PET imaging of these tumor types.(129) An l-type system is a reversible amino acid transport system;(130) tumoral effluxes of non-metabolized amino acid also occur, causing gradual washout of radioligand on dynamic PET images.(131) The system A (alanine-preferring) amino acid transporter deals with the transport of small aliphatic AAs, including serine, alanine, and glutamine. System A transports AAs with the N-methyl group.(132) Met gets incorporated into proteins, and it plays a role in transmethylation processes.(133) [1-11C] AAs have carbon-11 labeled at the alpha-carboxylate (−COOH) position. [1-11C]-Labeled natural AAs 11C-l-leucine ([11C]Leu) (41),(134)11C-l-methionine ([11C]Met) (42),(135)11C-l-phenylalanine ([11C]Phe) (43),(136) and l-[11C]tyrosine ([11C]Tyr) (44)(137) are involved in the synthesis of proteins and can be used to measure the rates of protein synthesis. [11C]Methionine gets highly accumulated in the malignant tumor cells compared with most normal tissues.(138,139) The [11C]MET (45) amino acid is one of the first amino acid tracers used.(140) Its uptake is mediated by LAT1 and has been extensively used for the detection of CNS tumors,(13,141−144) A correlation has been observed in decreased [11C]MET uptake over time post-therapy with long-term survival.(145) [11C]MET was demonstrated in detection, grading, delineation, and differentiating recurrences.(146) However, [11C]MET showed less sensitivity in studies with low-grade glioma,(13,147) Until now, there has not been much evidence about the utility of [11C]MET in tumor grading, as well as its role in differentiating tumor recurrences from radiation necrosis, which is quite controversial.(148−152) Though [11C]MET shows high sensitivity for gliomas, its use is limited because of false-positive results seen under benign conditions, such as instances of demyelination, leukoencephalitis, or abscess.(153) The diagnostic performance of MET PET is slightly lower, with an accuracy of roughly 75%,(152,154) and is most likely related to the higher affinity of MET for inflammatory processes.(155) [11C]MET is also reported as a PET tracer for prostate imaging with enhanced PSA levels.(156,157)
The ([11C]MCYS) (46), a PET tracer for tumor imaging, reportedly an analogue of 11C-MET, seemed to have potential value as a PET imaging agent for tumors.(158,159)[11C]MeAIB (47) is an N-substituted labeled non-natural amino acid that targets transport system A.(160,161) [11C]MeAIB is used for head and neck cancer imaging. Several non-natural AAs labeled at [1-11C], including [11C]ACPC (48), [11C]AIB (49), and [11C]ACBC (50), do not get integrated into protein synthesis and were used in some studies to image amino acid transport in a tumor.(162,163)[11C]5-HTP (51) is an amino acid PET tracer being successfully used in imaging neuroendocrine tumors and for the detection of early recurrence of small tumors.(164−166) This radiotracer is more sensitive to pancreatic-neuroendocrine tumors.(165) The efficient retention of [11C]5-HTP in neuroendocrine tumors is contributed by its uptake by the LAT1 transport system, decarboxylation by aromatic l-amino acid decarboxylase (AADC), and granular storage by vesicular monoamine transporters (VMATs).(167,168) [11C]Tyr (l-[1-11C-]-tyrosine), a carbon-11-labeled tyrosine kinase PET radiotracer, is used for detection and quantification in various tumor malignancies.(169−171) It enters the tumor cells via amino acid transport system l and largely gets incorporated into proteins, making it an appropriate molecular probe for rate quantification of protein synthesis. 11C-Tyr has an advantage over the [18F]FDG PET probe in cervical lymph node detection.(172)
The [11C]AMT (52) is one such example, and it has been used for imaging tumors by measuring AA’s transport rate.(173) [11C]AMT was originally developed for brain serotonin synthesis measurement,(174−177) later used in the detection of epileptogenic foci,(178−181) and currently explored in brain tumor PET imaging due to the tracer’s metabolism, which is related to tumoral immuno-resistance. AMT PET imaging uses AMT as the tracer, which is found to be accumulating in gliomas via the immunomodulatory kynurenine pathway, wherein the degradation of tryptophan causes the production of nicotinamide adenine dinucleotide (NAD+).(182) Some reports suggested the tumor immuno-resistance is due to high tumoral expression of indoleamine 2,3-dioxygenase (IDO) and the kynurenine pathway, which drew focus toward the use of AMT as a PET tracer for tumor imaging.(183,184) The results of kinetic analysis of dynamic [11C]AMT PET images provided a high accuracy in differentiating recurrent WHO grade II-1V gliomas from radiation injury.(185)
TSPO in tumor imaging: The translocator protein (TSPO) is an 18 kDa outer mitochondrial membrane protein. It is highly expressed during the process of neuroinflammation in the microglia and astrocytes.(186,187) Studies have shown upregulation of TSPO expression in astrocytic tumors, and TSPO imaging with [11C]PK11195 (53) detected the early anaplastic transformation in glioma.(188−192) The Su group used the [11C]PK11195 radiotracer and showed that dynamic PET imaging can differentiate low-grade astrocytomas from oligodendrogliomas(188) (Figure 7).
Figure 7
Figure 7. List of various target-specific carbon-11 radiotracers in oncology.
2.4.2. Cell-Based Therapy
Cell-based therapy is a rapidly emerging class of new therapeutics. Cell therapy is defined as the administration of live cell products to provide effector cells to treat disease or support other treatments. The principle of reporter gene imaging lies in the feature of imaging signals to the cells expressing the reporter gene.(193) Noninvasive molecular imaging with reporter genes is now translated into clinical imaging paradigms. However, reporter gene imaging is more confined in human subjects than in animals.(194) Trimethoprim, a highly specific small-molecule inhibitor labeled with carbon-11, was used to image genetically engineered cells required for cell-based therapy. This group synthesized 5-(3,5-dimethoxy-4 ([11C]methoxy)benzyl)pyrimidine-2,4-diamine ([11C]TMP) (54) and studied the biodistribution and sensitivity of 11C-TMP for E. coli dihydrofolate reductase (Ec dhfr) carrying cells in a xenograft mouse model. The results of the study showed that [11C]TMP rapidly accumulates in Ec dhfr carrying cells within minutes of intravenous administration. The [11C]TMP radioligand was capable of identifying less than a million xenografted cells in a small volume that is a clinically relevant number, providing advancement in current PET reporter gene technologies.(195)
3. PET Molecular Imaging Applications in Cardiology
ARTICLE SECTIONS
3.1. Oxidative Metabolism
Acetate, a two-carbon FA, is rapidly taken up by cells and converted into acetyl-CoA, which is utilized in the TCA cycle. [11C]ACE (40) was identified as an oxidative metabolism tracer.(196) The first study reported use of [11C]ACE to demonstrate the myocardial oxygen utilization in New Zealand rabbits.(197) The study also found out that, postadministration of [11C]ACE, the labeled CO2 efflux reflects myocardial oxygen consumption and it is slightly influenced by the changes in substrate utilization, i.e., <4%.(198) Another study used this tracer to study the myocardial oxidative metabolism and regional myocardial blood flow (MBF), thus determining myocardial efficiency in subjects with myocardial cardiomyopathy.(199) Another group simultaneously determined MBF and oxygen consumption with single data acquisition by using the [11C]ACE tracer.(200) The [11C]ACE radiotracer was also used to quantify the myocardial blood flow.(201) Nevertheless, the availability of [11C]ACE is limited by the short t1/2 of carbon-11 and its on-site production. Certain inorganic compounds, such as [13N]ammonia and [15O]water, are used for cardiac perfusion imaging.(202) The [15O]H2O freely diffuses into cardiomyocytes, while the uptake mechanism of [13N]NH3 is not clear. [15O]H2O is an ideal tracer for quantifying myocardial blood flow.(203)
3.2. Fatty Acid Metabolism
The myocardium requires high energy for contractile functions; hence, this energy is provided by FAs under normal conditions. Under ischemic conditions, FA oxidation is reduced, with increased glycolysis and glucose oxidation.(204) The metabolic signatures of the ischemic heart are decreased use of FAs and increased use of glucose; this feature is exploited in myocardial metabolism imaging.(205) FAs are broken down by β-oxidation in the mitochondria after getting activated to acyl-CoA. The acyl residues are further transferred into the mitochondrial matrix, the main regulatory site for FA oxidation.(206,207)[1-11C]Palmitate (55), a physiological tracer, is the first free fatty acid (FFA) introduced for imaging fatty acid metabolism of the heart(208) and can be used for evaluation of the enzymatic activity of carnitine-palmitoyl transferase I.(209) Prior studies reported that [11C]palmitate PET imaging showed the size of the defect and provided myocardial infarct quantification and its localization.(210) In an ischemic cardiomyopathic patient, the high zones of extremely depressing deposited [11C]palmitate indicated the link between cardiomyopathic state alteration in FA metabolism.(211) Myocardial ischemia, other cardiomyopathies, and cardiac tumors also show [18F]FDG uptake.(212,213)
3.3. Cardiac Neuroreceptors (β-Adrenoreceptor/β-AR)
The sympathetic adrenoreceptors β1 and β2 found on the myocardium are involved in the regulation of cardiac function. β1 receptors are richly present in normal myocardium, forming 80% of all β-receptors, but the β2-receptors are up to 50%.(214,215) The first radioligand [11C]CGP-12177 (56) is a hydrophilic, nonselective antagonist of β-receptors that had been used for cardiac PET adrenoreceptor imaging studies.(216) Because of radiochemical synthesis problems of [11C]CGP-12177, the [11C]CGP-12388 (57), an N-isopropyl derivative, was designed for clinical use.(217) The β-AR plays a vital role in heart failure, with low β-AR density being a direct indication of decreased contractility in the heart, which is an important hallmark of cardiac failure.
One research group has found that (S)-[11C]CGP-12388 could be used to detect the myocardial β-AR density and reported a greater reduction in β-AR density in idiopathic dilated cardiomyopathy.(218) [11C]CGP-12177 PET imaging can predict the cardiac function improvement in idiopathic dilated cardiomyopathy after long-term treatment with carvedilol.(219)18F-Fluorocarazolol is another tracer for the assessment of postsynaptic sympathetic neuronal functions through evaluation of β-AR density.
3.4. Myocardial Neuronal Imaging
3.4.1. Presynaptic Sympathetic Innervation
Cardiac autonomic nervous system PET imaging has been developed in the past decade, and various pre- and postsynaptic imaging agents have been used to explore the role of sympathetic dysinnervation at various stages of heart diseases.(220,221) Carbon-11-labeled meta-hydroxyephedrine ([11C]HED) (58) is a norepinephrine analogue, designed for PET imaging of sympathetic nerve terminals of the heart, and is used as an indicator of NE reuptake transporter (NET) density and synaptic NE levels.(222) A combination of fluorodeoxyglucose (FDG) viability imaging and [11C]HED imaging may prove helpful in detecting ischemic cardiomyopathy.(223) [11C]HED is a commonly used tracer for neuronal imaging of the heart. HED has a high affinity for NETs. HED myocardial retention is believed to be reliant on the continuous release as well as reuptake by NETs.(224) Studies showed an intense decrease in regional uptake of NE by sympathetic nerves with [11C]HED imaging in a pig model of hibernating myocardium.(225) [11C]HED PET imaging lacks accuracy in quantifying regional nerve densities because of rapid neuronal uptake rates. [11C]Epinephrine ([11C]EPI) (59) is a more physiological tracer, as it is continuously secreted from the adrenal medulla into the bloodstream. Although EPI is broken down by MAO, it is efficiently stored in the vesicles.(220) Hence, it is prevented from degradation, and the tracer is slowly cleared from the heart. Hence, the EPI was proved to complete flow of uptake, metabolism, and storage of neurotransmission, unlike HED where the primary target is the uptake-1 system, i.e., energy-dependent reuptake by neuronal NET without the action of metabolizing enzymes like MAO and COMT.(220)N-[11C]Guanyl-(−)-meta-octopamine ([11C]GMO) (60) has a much slower transport rate and confinement in storage vesicles.(226) The study stated the potential of [11C]GMO in the quantitative measurement of regional cardiac sympathetic nerve density and its ability to identify minimal sympathetic nerve loss. [11C]Epinephrine and [18F]fluorodopamine (a catecholamine derivative) were used to image the presynaptic sympathetic nervous system.(227,228)
3.4.2. Angiotensin II Type I Receptors (AT1-R)
PET imaging of myocardial AT1-R and CB1-R expression has grabbed attention due to its noninvasive identification of the myocardial receptors in different pathological changes that can serve as new biomarkers for cardiac risk.(229−231) The renin–angiotensin and kallikrein–kinin systems are systematically and locally functional in the myocardium.(232)[11C]KR31173 (61) was developed for visualization and quantification of myocardial AT1-R with a plan that it could provide exclusive cardiovascular prognostication in systolic heart failure patients.(233) The first study to explain the feasibility of [11C]KR31173 and PET/CT to image increased myocardial AT1-R in the myocardial infarction area was carried out in a rat model.(233) Though [11C]KR31173 and PET/CT showed good results in imaging and quantification of myocardial ATR-1 expression in both normal and abnormal conditions, further assessment and practicability of this method is necessary in different forms of heart failure.
3.4.3. Myocardial Cannabinoid Type 1 Receptor (CB1-R)
Endocannabinoids and cannabinoid (CB) receptors were primarily known for their importance in the brain function regulation, food intake, and energy balance. Their role has also been explored in the cardiovascular system.(234−236) Many studies revealed the CB1-R of endothelial cells of the coronary artery leads to causing stimulation of MAPK and spurt up reactive oxygen species and inflammation, which results in the development of atherosclerosis and cardiac dysfunction.(237) This may serve as a link between coronary endothelium function and cardiomyocytes, as well as possibly to myocardial receptor expressions.(238,239) A study showed that activation of myocardial CB1-R by endocannabinoids led to cardiac dysfunction via MAPK activation, angiotensin II receptor type 1 (AT1-R) signaling, and fibrosis.(229)[11C]OMAR (62), a specific radioligand utilized for brain PET imaging to find alterations in CB1-R such as in schizophrenia, was applied for PET imaging of the heart in the advanced obese state.(230) Due to the high lipophilicity of [11C]OMAR, it is taken up by the liver and reduces its uptake in the inferior and inferoseptal wall. This drawback of the [11C]OMAR radioligand characteristic increases the demand for a low lipophilic radiotracer with better imaging features(240) (Figure 8).
Figure 8
Figure 8. List of various target-specific carbon-11 radiotracers in cardiology.
4. PET Molecular Imaging Applications of Brain (Neurodegenerative Disorders, Addiction/Substance Abuse, Psychiatric Disorders, Epilepsy)
ARTICLE SECTIONS
4.1. Dopamine Transporters (DATs)
The dopamine transporters are sensitive to cocaine. It is a powerful addictive psychostimulant that binds to monoamine (DA, NE, and serotonin) transporter with micromolar to submicromolar affinity. Cocaine intoxication and addiction are facilitated mainly via dopaminergic pathways, with acute effects, due to inhibition of DA uptake by binding to the DAT.(241)[11C]Cocaine (63), an analogue of cocaine, binds to DAT and blocks the reuptake of DA, thereby increasing the intrasynaptic DA levels.(242) [11C]Cocaine in PET is employed to measure the density of dopaminergic neurons. Multiple PET imaging studies with [11C]cocaine demonstrated increased DAT for up to 6 weeks after the termination of cocaine use.(243,244) However, the [11C]cocaine PET imaging for measurement of dopaminergic neurons reflected no long-term changes in DAT due to cocaine use.(243) The Volkow group observed decreased uptake of tracer along with reduced distribution volume in the basal ganglia, cortex, thalamus, and cerebellum in the brain of detoxified cocaine abusers compared to controls, with no DAT changes in availability.(244,245) The β-[11C]CIT (64) PET radioligand which has specificity for DAT showed a 50% reduction of DAT availability in the striatum of Huntington’s disease (HD) patients compared to control subjects.(246)[11C]PE2I (65) showed high affinity, specificity, and selectivity binding to central DAT by displacement experiments in the monkey brain in vivo.(247) In this study, [11C]PE2I reached a peak equilibrium fast and gave a high signal-to-noise ratio in the striatal area as well as in the thalamic brain region. Results hinted at the suitability of the [11C]PE2I tracer for quantification of both striatal and substantia nigra DAT in man. Varrone et al. performed a direct comparison of quantification of the DAT in the rhesus monkey.(248) Results showed that [18F]FE-PE2I displayed faster kinetics and more metabolism than [11C]PE2I. Major limitations for clinical usage of [11C]PE2I, especially for individuals suffering from neurodegenerative disorders and movement disorders, include a long scan time as well as the need for a structural MRI for reference region definition involving an additional scan. Besides, it adds additional costs for the health care system.(249) Jonasson demonstrated [11C]PE2I data along with the SVCA extracted reference time–activity curve (TAC) could discriminate between normal controls and Parkinsonian patients suffering from degeneration of DAT availability in the putamen. Also, [11C]PE2I scans reduce radiation exposure to the patients by 70% compared to dual-scan with [18F]FDG and [123I]FP-CIT.(250) In idiopathic PD and atypical Parkinsonian disorders, unambiguous clinical diagnosis is difficult to achieve due to different degrees of alteration in the central dopaminergic and overall brain functional activity. [18F]FE-PE2I and [18F]FECNT are the two new most characterized PET tracers for DAT imaging which allowed the DAT quantification in both striatum and substantia nigra.(251)
4.2. Vesicular Monoamine Transporter Type 2 (VMAT2)
VMAT2 protein involves in the monoamines transport into synaptic vesicles. Postsynthesis of DA from l-DOPA in the nerve terminal, the neurotransmitter is transported and stored in the vesicles via VMAT2 receptors. [11C]Dihydrotetrabenazine ([11C]DTBZ) (66) showed its potential in imaging this decrease in VMAT2 receptors in PD patients.(252,253) [11C]DTBZ (selective to VMAT2) showed reduced binding in HD patients compared to controls.(254) A study showed a strong correlation between the density of striatal VMAT2 and the nonmotor symptoms of PD.(255) [11C]DTBZ and [18F]FP(+)-DTBZ are the main VMAT2 tracers. [18F]FP(+)-DTBZ targets VMAT2 receptors and is used for the diagnosis of PD.(256) Moreover, [18F]FP(+)-DTBZ provides various advantages; e.g., it is useful in the assessment of PD severity, and also, it is less affected by compensation or pharmacological regulation. Also, [18F]FP(+)-DTBZ, [18F]florbenazine, and [18F]AV-133 are VMAT2 selective and provided the protein density quantification in various clinical studies.(257−259) [11C]DTBZ is a specific VMAT2 radiotracer for PD diagnosis.(260) In comparison to [11C]DTBZ, [18F]FP(+)-DTBZ has an affinity for VMAT2 and shows lower fat solubility, providing a lesser nonspecific binding.(261) 10-(+)-[11C]DTBZ is a derivative of DTBZ, which was synthesized and evaluated via in vivo imaging for VMAT2 using micro PET study.(262)
4.3. Dopamine Receptors
Dopamine D1 receptors play an important role in schizophrenia, cognitive disorders, and PD. [11C]NNC-112 and [11C]SCH23390 are widely used in clinical studies.(263−267)[11C]NNC-112 (67) is a derivative of [11C]SCH23390; it was used in PET imaging in the zQ175 HD mouse model and wild-type mice with the diseased animals expressing less D1 receptors in the specific areas and in patients with major depressive disorder (MDD) compared with normal individuals.(268,269) The [11C]NNC-112 radioligand PET study showed a low D1 receptor binding in the ventral striatum with increased self-administration of cocaine, indicating the role of this receptor and its contribution in enhancing the risk of relapse.(270)[11C]SCH23390 (68) is a well-known potent halobenzazepine-based D1 receptorantagonist.(271) A study was performed on HD-affected patients and reported a 50% reduction in D1 receptor density in the putamen of affected subjects compared to normal volunteers.(272) A study was conducted involving a larger group, including asymptomatic, symptomatic, and diseased subjects along with healthy control subjects, to determine the rate of loss of D1 and D2 receptors in HD over a period of 40 months.(273) Another group observed a decline in BPND (nondisplaceable binding potential) in the frontal cortex, except for the striatum in BD patients, who were not under medication for 2 or more days before the scan.(274) The specificity of [11C]SCH23390 for the D1 receptor is low, thus restricting its utility as a tool to measure the receptor density in the extrastriatal sites of the brain, such as the frontal cortex which has a receptor density lesser than that in the striatum. A [11C]SCH23390 imaging study in MDD patients with anger demonstrated a 13% decline in tracer binding in the striatal region.(275)
D2 and D3 receptors are involved in PD, schizophrenia, anxiety, or drug addiction. [11C]Raclopride, [11C]FLB-457, and 18F-fallypride are D2/D3 nonselective antagonists. [11C]MNPA, [11C]NPA, or (+)-[11C]PHNO are proven to be the suitable tracers for the study and diagnosis of disorders associated with enriched dopamine levels. [11C]Raclopride (4), a benzamide analogue having moderate affinity and reversible binding, is the most commonly used PET tracer for dopamine D2 receptor imaging.(276,277) Studies to measure D2 receptors with [11C]raclopride in HD patients explained the thalamic involvement in both premanifest and manifest HD.(278) Follow-up PET imaging studies demonstrated that reduction in [11C]raclopride binding occurs progressively in HD(279−281,273) and also in the premanifest HD.(282) The [11C]raclopride PET study was performed in symptomatic and asymptomatic HD mutation carriers and healthy controls, and a positive correlation was observed.(283,284) [11C]Raclopride is a common antagonist of D2/3 receptors used for Parkinsonian patients.(285) [11C]Raclopride PET imaging has reported the role of D2 receptor binding as a biomarker, as its decrease predicts a pleasurable response to the psychostimulant drug methylphenidate in healthy nonaddicted subjects,(286) thus increasing the addictive liability of stimulants for these subjects. Nonalcoholic members with a family history of alcohol addiction have increased D2 receptor binding.(287)[11C]FLB-457 (69) is a high-affinity D2/D3 receptor PET radiotracer, which can be used to assess cortical (extrastriatal) dopamine receptors.(288−291) No differences were observed in extrastriatal D2/D3 receptor binding using [11C]FLB-457 radioligand in major depressive disorder (MDD).(292,293) A study demonstrated low D1 and D2 binding in caudate and putamen of HD patients compared to normal control by using [11C]raclopride and [11C]SCH23390 radioligands.(294)N-[11C]Methylspiperone ([11C]NMSP) (70), a D2 receptor family radioligand, showed increased Bmax in the caudate region of unmedicated bipolar disorder (BD) patients with psychosis.(295,296) In PD and Levodopa-induced dyskinesia (LID), [11C]raclopride PET imaging was the gold standard for D2/D3 receptor density examination.(297) The limitations of the [11C]raclopride are that it fails to distinguish between D2 and D3 receptors due to the relative abundance of D2 receptors over D3. Also, [11C]raclopride results have been inconclusive when PD-LID is considered.(298−301) Payer et al. demonstrated (+)-[11C]propyl-hexahydro-naphtho-oxazin ((+)-[11C]PHNO) (12) binding in the D3-rich globus pallidus of PD patients, especially those with LID.(302) These findings suggested that D3 overexpression is a feature of PD-LID, as one-third of globus pallidus DA receptors are D3(303) and also a maximum of globus pallidus (+)-[11C]PHNO signal comes from D3 in healthy subjects.(304) Payer et al. revealed that there was no D3 receptor level upregulation in PD patients with impulse control disorders (ICDs).(305) Besides, no D2 receptor level changes were noticed in ICD and non-ICD groups. The results are contrary to the findings that D2/3 receptor level changes are involved in the development of ICD in PD.
The difference measured by performing a [11C]raclopride scan followed by administration of AMPT (alpha-methyl-p-tyrosine), a tyrosine hydroxylase inhibitor, showed a reduction in the endogenous dopamine in individuals with DSM-IV cocaine dependence.(306) Decreased endogenous dopamine release in DSM-IV alcohol-dependent individuals compared with healthy controls was reported by [11C]raclopride PET scan before and after a psychostimulant challenge to measure the presynaptic dopamine release.(307)
4.4. MAO Expression
The function of the MAO enzyme is to oxidize DA in the presynaptic neuron. Chlorgyline and deprenyl are the two suicide enzyme inhibitors that block the dopamine oxidation and elevate the DA levels in the nerve terminal. Deuterium-substituted derivatives such as [11C]clorgyline (71) and l-[11C]deprenyl (72) have been used as imaging agents to determine the expression of MAO-A and MAO-B in human subjects.(308,263) [11C]Deprenyl and [11C]deprenyl-D2 (73) are the only two tracers that have been developed for MAO-B imaging.
4.5. Adenosine Receptors
Adenosine receptors (ARs) are considered as biomarkers of HD pathology because of their role in neurotransmission.(309) It works by using four G-protein-coupled receptors—A1, A2A, A2B, and A3. Dynorphinergic medium spiny neurons (MSNs) express A1 receptors which also express D1 receptors. A2A along with D2 receptors are coexpressed in enkephalinergic MSNs.(310) [11C]KF18446 (74), a xanthine-based ligand, reported a noticeable decline in the density of A2A receptor in HD patients.(311,312) [11C]KF18446 PET imaging results showed degeneration in the A2A receptor along with D1 and D2 receptors.(311)[11C]MPDX (75) is one of the most studied xanthine derivatives utilized for various studies.(313−315) [11C]MPDX was used to evaluate A1AR changes in patients with chronic diffuse axonal injury(314) and also to study the density of A1ARs in early stage PD patients.(315) Recently, A2A AR antagonists [11C]TMSX (76) and [11C]preladenant (77) have been studied.(316−318)[18F]CPFPX (78) has been widely used for the development of suitable pharmacokinetic models for cerebral A1AR quantification.(319) Other structurally related derivatives of [18F]CPFPX named CBCPM and others have also been developed and preliminary PET studies carried out.(320,321)
4.6. Phosphodiesterase 10 (PD10)
Phosphodiesterase 10 (PD10) is abundantly expressed by the MSNs and is involved in dopaminergic and glutaminergic neurotransmission. [11C]IMA-107 (79), a selective PD10 radioligand scan, was performed to look into a cohort of manifest HD subjects with further probability. The enhanced uptake was observed in motor thalamic nuclei in comparison to control subjects, indicating the role of PD10 alterations several years before the onset of HD symptoms.(322) Future studies can contribute to determining the role of PD10 PET imaging as a possible biomarker to monitor HD progression, as well as to evaluate PD-oriented treatments. Reduction in PDE10A expression in the striatum was observed in transgenic R6/1 and R6/2 mice models of HD before the development of motor impairment.(323) Carbon-11-labeled papaverine is the first PDE10A PET radiotracer radiolabeled and evaluated in 2010.(324) However, its usage is limited by low retention in the brain. [11C]TZI964B (80) radioligand studies have shown promising results(325) following which several compounds have been synthesized for 18F-labeling, as it provides several advantages over carbon-11 radiotracers. [18F]TZ19106B and [18F]TZ8110 are the two new potent compounds that have been studied.(326,327)
4.7. Synaptic Vesicle Protein 2A (SV2A)
Synaptic vesicle glycoprotein 2 (SV2) is a candidate marker for synaptic density. In rats and humans, three isoforms of SV2 are expressed, such as SV2A, SV2B, and SV2C.(328,329) The 2A isoform is extensively found in synaptic vesicles of the CNS.(330) SV2A, a transmembrane protein, is expressed ubiquitously in almost all brain synapses, situated in synaptic vesicles, and functions as a transporter regulating the exocytosis of a synaptic vesicle, or altering the function of the synapse.(331)[11C]UCB-J (81) is a suitable PET tracer for human studies.(332,333) [11C]UCB-J, an SV2A, is the first in vivo marker of synaptic density discovered.(334) The Chen group reported the reduction in synaptic density in the medial temporal lobe of AD patients in comparison with normal subjects on assessment with [11C]UCB-J PET imaging.(335) [11C]UCB-J showed a higher uptake and faster kinetics in non-human primates and rat studies.(336) One research group used this [11C]UCB-J for the first time in a PET study in an HD animal model, and more studies need to be evaluated.(337)
4.8. Glutamatergic Receptors
Alteration in the metabotropic glutamate receptor (mGluR) was noted in presymptomatic HD mice.(338)[11C]ABP-688 (82) is a selective mGluR5 antagonist; the radioligand PET imaging was performed in the Q175 mouse model of HD to perform a longitudinal study of mGluR5 receptor changes.(339) The role of mGluR5 in AD pathology and its scope as a major therapeutic target has encouraged research on its expression monitoring and receptor binding in AD models. [11C]ABP-688 radioligand PET imaging was performed in AβPP (amyloid-beta precursor protein) transgenic mice (tg-ArcSwe), and the results displayed no difference in binding in comparison to wild-type mice.(340) One research group carried out ex vivo autoradiography, biodistribution, and PET studies with [11C]ABP-688 on rats, wild-type mice, and mGluR knockout mice.(341) PET studies on rats and wild-type mice showed radioactive uptake in the mGluR5-rich regions of the brain, whereas the homogeneous distribution of radiotracer in mGluR5 knockout mice indicated the specificity of [11C]ABP-688 radiotracer toward mGluR5. One study was performed to evaluate the mGluR5 distribution volume ratio in schizophrenia patients and compare it with the healthy subjects.(342) The results showed no difference in the mGluR distribution volume ratio in the schizophrenia patients’ brains and normal subjects. However, a marked global reduction in mGluR distribution volume ratio in healthy subjects with smoking habits was noted. Treyer et al. reported decreased mGluR5 binding of [11C]ABP-688 tracer in the hippocampus and amygdala in Alzheimer’s dementia subjects’ brains.(343) This reduction in mGluR5 binding could be either due to loss of postsynaptic binding sites or adaptive processes in AD that need to be explored in further studies. Ametamey et al. studied the use of [11C]ABP-688 tracer for mGluR5 imaging in human brains.(344) Results showed the highest [11C]ABP-688 uptake in mGluR5-rich regions of the brain.
4.8.1. NMDA Receptors
The NMDA modulators are proven to be the effective ligands for the treatment of various neurological disorders, cerebral ischemia, neuropathic pain, and psychiatric illnesses, such as depression and schizophrenia.(345)[11C]Me-NBI (83) PET tracer was designed to image GluN1/GluN2B containing NMDA receptors. A recent study has shown that only the (R)-enantiomer of [11C]Me-NB1 is more potent toward NMDA receptors. In contrast, the (S)-enantiomer of [11C]Me-NB1 showed considerable binding to sigma1 receptors.(346) Activation of NMDA receptors results in the increased Ca2+ influx into cells; however, very high levels of Ca2+ lead to cell death. [11C]Me-NBI was used in live rats to evaluate the dosage and usefulness of eliprodil (NMDA Glu2B receptor blocker).(347) The results of this investigation showed that, at neuroprotective doses of eliprodil, GluN1/GluN2B NMDA receptors are fully occupied.
4.9. Opiate Receptors
There are three subtypes of opiate receptors, such as μ, δ, and κ. [11C]Diprenorphine (84), a nonselective partial agonist for the μ, δ, and κ receptors, showed low binding in the caudate and putamen of HD patients.(348) [11C]diprenorphine and [11C]buprenorphine (85) were designed for opiate receptor imaging studies with agonist and antagonist properties. [11C]GR103545 (86), a potent κ-opioid receptor agonist, GR89696, reported remarkable kinetic values.(349)[11C]Carfentanil (87) was the first tracer studied for opiate receptor imaging.(350,351) A study reported the [11C]carfentanil radioligand and showed increased μ-opioid binding in several regions of the brain of cocaine addicts for several weeks after cocaine abstinence, suggesting an association between craving and increase in μ-opioid binding.(352) The first study to detect the involvement of the endogenous opioid in cocaine dependence and craving in cocaine addicts using [11C]carfentanil PET radiotracer showed the increased binding potential of μ-opioid receptors in various brain regions, after 1–4 days since the last cocaine use by the subjects. This increased binding potential lasted after 4 weeks of substance abstinence in the frontal cortex, thalamus, caudate, and cingulate.(352,353) Variable results have been observed by researchers by using [11C]methylnaltrindole (88) (selective for the μ-opioid receptor) or [11C]diprenorphine as PET tracers to study the opioid transporter, with results either showing increased or decreased striatal binding.(354)
4.10. GABA Receptors
GABA (γ-amino-butyric acid) receptors which are widespread in the cortex interact with GABA. Two types of GABA receptors are known, GABAA and GABAB. The GABAA receptor complex consists of a central benzodiazepine (BDZ) receptor. [11C]PK-11195 (53), a tracer for the peripheral benzodiazepine receptor (PBR), binds only to activated microglia.(355) Radioligand [11C]DPA-713 (89) from the pyrazolopyrimidine class shows more affinity toward PBR compared with PK11195. [11C]Flumazenil (3) (GABAA receptor ligand) was used in amyotrophic lateral sclerosis (ALS) patients to study the correlation between loss and cortical hyperexcitability of GABAergic transmission. The results showed a widespread reduction in binding in ALS individuals compared with controls.(356,357) A group hypothesized a reduction in GABA-benzodiazepine (GABA-BDZ) receptor function in alcohol-dependent individuals. A [11C]Flumazenil PET scan was performed by them to explore the in vivo association between the BDZ receptor and midazolam.(358) [11C]Flumazenil (FMZ) is often used to monitor the GABAA receptor to understand the pathogenesis of epilepsy.(220) The GABAA α5 subtype receptor is extrasynaptic and is involved in learning, memory, and addiction. Jim and colleagues used a [11C]Ro-15-4513 (90) PET radiotracer to study this receptor subtype in humans and reported that this tracer has about 60–70% specificity toward α5-rich regions.(359)
4.11. Serotonergic System
Serotonin is produced in the dorsal raphe nucleus of the brain, which has widespread innervations in the neocortical areas. [11C]5HTP (51), which was initially synthesized to monitor serotonin metabolism, later found its utility in neuroendocrine tumor imaging. [11C]AMT (52) was reported to indirectly evaluate serotonin synthesis.(360) A postoperative 11C-AMT PET imaging study has provided knowledge about brain plasticity postcortical resection in epilepsy patients. Increased uptake of AMT has been observed in the ipsilateral lentiform nucleus compared to the contralateral side after removal of epileptic brain tissue, thus putting forth functional reorganization of cortical–striatal projections linked with increased expression of serotonin.(361) There are 14 known subtypes of the serotonin receptors.(362) Still, an enormous amount of focus is on the development of radiotracers for the serotonin receptor subtypes.(363)
The serotonin 5-hydroxytryptamine (5-HT1A) receptor is widely expressed in the cortex region of the brain.(364)[11C]WAY100635 (91), a 5-HT1A receptor antagonist, is the first radioligand used in human imaging. The [11C]WAY100635 (a 5-HT1A ligand) PET radiotracer showed reduced binding in the specific regions of the brain in nondepressed ALS patients when compared with normal subjects.(365) [11C]WAY100635 radioligand PET imaging was performed to monitor the 5-HT1A receptor binding in AD-dementia patients.(366) In patients with temporal lobe epilepsy (TLE), the [11C]WAY100635 radioligand showed a low affinity to 5-HT1A in the TLE foci.(367) To prevent in vivo metabolism of this tracer, carbon-11 was labeled in a different position and the carbonyl-[11C]desmethyl-WAY100635 (DWAY) (92) analogue was synthesized, with excellent 5-HT1A receptor binding.(368) The [11C]NMSP (93) (an irreversible antagonist) radioligand binds to the 5-HT2A receptors in the frontal cortex.(369)[11C]MDL (94) imaging demonstrated elevated binding potential in the regions of frontal, parietal, and occipital cortices of MDD patients with remittance.(370,371)
The serotonin transporter (SERT) is located on the axons and terminals of serotoninergic neurons projecting from the raphe nuclei. SERT can be considered as a more definite marker of serotonergic terminals than 5-HT1A and 5-HT2A receptors, located also at the non-serotoninergic nerve terminals.(372)(+)-[11C]McN5652 (95) has certain drawbacks, such as its properties of in vivo metabolism, nonspecific binding, and a poor signal contrast, that restrict its application. A study used the (+)-[11C]McN5652 radioligand for PET imaging to monitor the density of SERT.(373) Other radiotracers with a high selectivity for serotonin transporters are [11C]DASB (96) and [11C]MADAM (97). These tracers have shown admirable results in SERT imaging in human brains.(374,375) To monitor the SERT binding, a group conducted an [11C]DASB imaging study in AD-dementia patients and healthy volunteers and reported reduced SERT binding in the midbrain, nucleus accumbens, putamen, and thalamus.(376,377)
4.12. Kynurenine Pathway
AMT is an analogue of tryptophan (Trp). Besides being metabolized by tryptophan hydroxylase, Trp is metabolized by tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase via the kynurenine pathway in the brain. Under normal physiological conditions, kynurenine pathways do not cause the accumulation of [11C]AMT in the brain, while it has been reported that, following ischemic brain injury or immune activation, there is an enhancement of quinolinic acid (a metabolite of the kynurenine pathway) in the brain, thus indicating the importance of the pathway in disease pathogenesis. The involvement of the kynurenine pathway in tuberous and epilepsy patients has also been well established.(378) The [11C]AMT radioligand traces tryptophan metabolism via serotonin or kynurenine pathways. Out of various molecular probes, [11C]AMT is the one radiotracer that is taken up by the epileptogenic focus in the interictal state, which otherwise shows normal scans in MRI and glucose metabolism PET. Some other PET tracers that have been used to detect epileptogenic focus are flumazenil (3), [11C]PK11195 (53), [11C]diprenorphine (84), and [11C]NMPB (101), but none has been of such effect. AMT PET guides resection with a maximum specificity and sensitivity.(379) [11C]AMT is the only tracer that can be used for identification and delineation of epileptogenic focus in their interictal state.(380) Various studies have emphasized the role of [11C]AMT PET in studying the neurobehavioral features of TSC, like autism, ADHD, and cognitive impairment.(379) Several studies have reported increased uptake of AMT in different types of cortical developmental malformations in patients with focal cortical dysplasia, subependymal heterotopia, congenital perisylvian syndrome, and polymicroglia.(381,382)
4.13. Cholinergic System
Acetylcholine neurotransmitter is involved in learning, memory, and AD. The cholinergic receptors as well as the enzymes involved in the synthesis and termination are the main targets for a valid radiotracer development utilized in imaging studies. The nicotinic class of acetylcholine receptors are ligand-gated ion channels located at the transmembrane site. Nicotine acts on nicotinic-cholinergic receptors (nAChRs), which are abundantly located in the CNS, PNS, and adrenal glands. Nicotinic receptor subtype α4β2 has been shown to have the highest affinity for nicotine.(263) The [11C]nicotine (98) radioligand showed high binding in various cortical and subcortical regions, and low binding was noted in other areas. Its clinical application is limited due to the high rate of nonspecificity, as well as due to the rapid washout of the tracer. Other carbon-11-labeled derivatives such as epibatidine, a potent analgesic, which is a toxic alkaloid obtained from Ecuador poison frog, has a high specificity for nAChRs. However, due to its toxic properties, it is unsuitable for human use. Therefore, various synthetic derivatives are underway to overcome the limitations.(383) [18F]ASEM is the first reported highly specific PET imaging agent for human α-7-nAChR receptors.(384,385)
Muscarinic receptors (mAChRs) are the most frequently found postsynaptic cholinergic receptors in the brain. Several PET pharmaceuticals, such as [11C]QNB (99), [11C]TKB (100), [11C]NMPB (101), [11C]scopolamine (102), and [11C]benztropine (103), utilized to image mAChRs did not show selectivity for its receptor subtypes. These receptors showed high binding in the areas of the cortex, striatum, thalamus, and pons. [11C]NMPB showed lower muscarinic receptor binding in neocortical areas and the thalamus with normal aging, but no specific changes were observed in AD brains,(386) while [11C]NMPB imaging showed hypersensitivity of mAChRs in the frontal cortex of PD patients.(387)
Acetylcholinesterase (AChE) enzymes function by hydrolyzing Ach, in turn regulating the concentration of ACh neurotransmitter in the synapse. Physostigmine, an inhibitor of AChE, enhances the level of ACh neurotransmitters in the synapse. The [11C]phytostigmine ([11C]PHY) (104) radiotracer uptake and retention indicated the AChE enzyme activity.(388) Certain analogues of ACh, that are substrates of AChE, such as MP4A/AMP show specificity of 94% for AChE in the brain of humans.(389) Reduced uptake was reported in AD brains in all cortical areas, with temporal and occipital cortices being most severe, whereas, with preserved uptake in the basalis of Meynert, on using analogues of ACh and substrates for AChE such as [11C]MP4P (105) and [11C]MP4A (106). This observation further suggested the phenomenon of “dying back” with cholinergic impairment beginning in the cortical areas and slowly affecting the cells of the basal nuclei.(375)
4.14. Amyloid Plaques
Aβ plaques are the hallmarks of AD. Different chemical classes of amyloid tracers are available, such as thioflavin T which includes [18F]flutemetamol, [11C]PIB, and [11C]AZD2184; stilbenes including [18F]AV-45, [18F]AV-1, and [11C]SB-13; benzoxazoles including [11C]BF-227 and [18F]BF-227; and benzofurans such as [18F]AZD4694. Pittsburgh compound B (PIB), also known as [11C]6-OH-BTA-1, was prepared based on the thioflavin-T amyloid dye.(390) Another Aβ PET tracer such as [11C]A2D-2184, on clinical evaluation, showed faster kinetics in humans.(391) The most commonly used PET tracer for Aβ imaging is [11C]Pittsburgh compound B ([11C]PIB) (107), as it showed proper retention in specific regions linked with AD amyloid pathology, while fluorine-18-labeled FDDNP binds to neurofibrillary tangles (NFTs) as well.(392) The first human PET study with [11C]PIB was carried out in 2004. An increased association between [11C]PIB cortical retention and cerebral glucose metabolism determined with [18F]FDG was most prominently observed in the parietal lobes.(393) A study reported high correlation between the binding properties of [18F]florbetapir and [11C]PIB PET in AD patients, supporting the general hypothesis that these agents generally provide analogous information.(394) Another study showed similar correlations between fluorine-labeled PIB derivative [18F]flutemetamol and [11C]PIB PET in AD patients, amnestic MCI patients, as well as healthy volunteers.(395) [11C]PIB, [18F]flutemetamol, [18F]amyvid, and [18F]florbetaben have been extensively developed for amyloid imaging. Though all of these compounds display high cortical uptake in amyloid-positive patients, nonspecific white matter binding is also observed in amyloid-negative patients.(396)[11C]SB13 (108) (stilbene) reported the same regional brain distribution pattern as PIB in AD patients and healthy controls.(397)
4.15. Tau (τ) PET Imaging
Normal physiological tau maintains the stability of microtubules. Tau consists of six isoforms in the brain, with either three or four repeats denoted as 3R or 4R of the microtubule-binding domain.(398)[11C]PBB3 (109), a first-generation τ PET radiotracer, showed favorable kinetics and high affinity to the 3R/4R tau isoform combination, which is typical in AD.(399) A study has also reported that extracellular amyloid shows no correlation with cognitive status in AD.(400) Strikingly, in the same work, a correlation between the intracellular tau NFT burden with cognitive decline was noted. The above observation hinted that tau NFTs could be a viable target for AD therapy and PET imaging of AD. Additionally, tau NFTs are involved in a variety of other dementia subtypes, including FTD, PSP, and CBD. A few studies suggested the quinolines and benzimidazoles as scaffolds of interest for tau protein.(401) The quinoline scaffold [18F]THK523 showed affinity and specificity for tau over Aβ.(402,403) Other tau tracers, such as [18F]T808 and [18F]FDDNP, showed an affinity for both tau and Aβ. A group synthesized N-[11C]methyl lansoprazole (110), performed a preclinical evaluation, and confirmed the affinity for tau NFTs.(404) A group discovered three novel tau PET tracers, such as [11C]R06924963 (111), [11C]R06931643 (112), and [18F]R06958948. These tracers showed a high affinity for tau NFTs and high selectivity against Aβ plaques.(405) Due to the mixed nature of pathology, any novel tau PET tracer should mandatorily show selectivity for Aβ plaques. However, the first clinically evaluated [18F]FDDNP PET tracer showed limited uses as tau aggregates’ biomarker, though it showed a high affinity for Aβ plaques (Figure 9).
Figure 9
Figure 9. List of various target-specific carbon-11 radiotracers for brain imaging.
5. PET Molecular Imaging Applications in Neuroinflammation
ARTICLE SECTIONS
5.1. Translocator Protein (TSPO)
TSPO is an outer mitochondrial membrane protein of molecular weight 18 kDa highly expressed in activated microglia, due to a number of factors.(406−408) There are different TSPO radioligands such as (R)-[11C]PK11195 (53) with high lipophilic and low specific binding,(409) The [11C]DPA-713 (89) radioligand shows 10 times higher binding potential than (R)-[11C]PK11195(410) and [11C]PBR28 (113) with much better in vivo imaging features than (R)-[11C]PK11195. A group reported the first PET study of (R)-[11C]PK11195 and noted an increased tracer uptake in AD subjects.(411) Studies showing glial activation in mild cognitive impairment (MCI) patients preceding clinical AD have been conducted.(412) Studies conducted(413,414) using the (R)-[11C]PK11195 PET radiotracer showed reduced binding in MCI patients but increased binding in clinical AD patients. A group observed a moderate increase in [11C]PBR28 uptake in AD patients with worsening clinical representation.(415)[11C]AC-5216 (114), a second-generation TSPO radioligand, was used in the transgenic PS19 mice model of tau pathology to study AD. The results showed that the [11C]AC-5216 tracer uptake was linearly proportional to the phospho-tau immunolabeling.(416) Studies have also been conducted on alternatives to TSPO ligands using cannabinoid 2 receptor tracers, including [11C]SCH225336 (68) and [11C]A-836339 (115).(417−419)
[11C]PBR28 (aryloxyanilide ligand), a second-generation TSPO ligand, showed higher specific binding than (R)-[11C]PK11195(407) in several CNS disorders such as epilepsy, AD, and MS.(420,408,421) [11C]DPA-713 (pyrazolopyrimidineacetamide ligand), a second-generation TSPO radioligand, also showed higher specificity than the first-generation (R)-[11C]PK11195 radioligand in distinguishing lesioned brain from the healthy normal brain in a rat neurodegenerative model.(422) A group reported the [11C]DPA-713 radiotracer to accurately quantify neuroinflammation.(423) (R)-[11C]PK11195 PET imaging showed higher binding in individuals affected with Rasmussen encephalitis or focal cortical dysplasia (FCD) but not in TLE patients.(424,425) A group has explained the high TSPO in both temporal and extra-temporal regions in TLE patients.(407)
The (R)-[11C]PK11195 TSPO PET radioligand was used to image the brain of four progressive supranuclear palsy patients, and all of them showed greater binding in specific regions compared to control patients.(426) Another study on 16 PSP-Richardson syndrome patients also showed higher binding of (R)-[11C]PK11195 tracer compared to control subjects in the specific regions of the brain.(427) (R)-[11C]PK11195 studied in the brain of four corticobasal degeneration also showed increased uptake in the specific regions.(426) The first-ever study with (R)-[11C]PK11195 on frontotemporal dementia patients showed an increase in uptake in the left dorsolateral prefrontal cortex (PFC), right hippocampus, right parahippocampus, and bilateral putamen in comparison to normal subjects.(428) The second study which was performed using [11C]PBR28 in four FTD patients showed increased binding and also reported a lack of comorbid AD pathology with amyloid PET.(429) Higher regional binding was observed in HIV+ subjects (cognitively impaired and unimpaired) in comparison to healthy controls, while the highest binding was noted in patients with HIV-associated dementia using (R)-[11C]PK11195 PET.(430) The results varied in other studies. With second-generation tracers like [11C]DPA-713 or [11C]PBR28, increased regional binding was noted in virally suppressed HIV+ individuals. HIV associated dementia with [11C]DPA-713 showed higher frontal cortex binding,(431) and [11C]PBR28 also showed region-specific binding and its association with poor performance and verbal learning and memory.(432) A fully quantitative study of TSPO with [11C]PBR28 showed higher binding in TLE patients for both ipsilateral and contralateral temporal regions.(407) One case report demonstrated increased [11C]PBR28 binding in the subacute lacunar infarction.(433) Hemorrhagic stroke PET imaging of neuroinflammation is rarely studied, unlike acute or subacute stroke. One study with (R)-[11C]PK11195 showed decreased uptake in hematomas.(434) Increased TSPO binding with (R)-[11C]PK11195 was first observed in the motor cortex and associated brain regions of ALS patients;(435) the results were reproduced with second-generation TSPO radioligands as well. A therapeutic trial of [11C]PBR28 PET in ALS subjects showed no difference.(436)
5.2. Glycogen Synthase Kinase 3 (GSK-3)
It is a serine/threonine kinase consisting of isoforms GSK-3α and GSK-3β. GSK-3β is highly expressed in the neural tissue and is involved in the regulation of brain development. PF-367 (selective inhibitors of GSK-3) when tagged with carbon-11 showed a high binding signal in the brain because of high BBB penetration and considerable selectivity for GSK-3, making [11C]PF367 (116) a lead neuroimaging agent for GSK-3.(437)
5.3. Cannabinoid-2 Receptor
Cannabinoid-2 receptors are G-protein-coupled receptors and are involved in immunomodulation and endogenous response to injury.(438) A study suggested the high expression of CB2 receptor protein in Aβ plaques in AD brain tissues in comparison to healthy individuals with immunohistochemical studies.(439) Biodistribution studies in mice with [11C]MA2 (117), a radiotracer with CB2 selectivity, showed high brain uptake and good clearance.(440) The oxadiazole derivatives [11C]MA2 and [18F]MA3 and thiophene-based tracers [11C]AAT-7782 (118), [11C]AAT-015 (119), and [18F]FC0324 show high affinity toward the CB2 receptor but suboptimal selectivity over the CB1 receptor. Studies using [11C]RS-028(441) (120) and [11C]KD2(442) (121) have shown higher and specific binding on ALS spinal cord tissues compared to that from healthy controls.
5.4. Purinergic Receptors
The P2 family of receptors mediates purinergic signaling, which plays a major role in the nervous system physiology.(443) Biodistribution studies with a radioligand [11C]A-740003 (122), selective for the P2X7 receptor in healthy rats, showed low uptake.(444) Another radioligand [11C]JNJ-54173717 (123) with potent P2X7 receptor antagonist property, when used in biodistribution studies in normal rats, easily crosses the BBB and shows clearance from plasma.(445)[11C]GSK1482160 (124), [11C]A-740003, and [11C]JNJ-54173717 are the three novel PET tracers developed for P2X7. Only [11C]JNJ-54173717 showed prominent features for in vivo evaluation and will be under clinical evaluation in the future.(445) The first potential P2Y12-receptor-based PET tracer is [11C]2 which showed very low brain uptake disfavoring its use for PET scans.(446) A preliminary study with the [11C]JN5717 P2X7 radioligand in ALS patients showed no increase in uptake.(447)
5.5. Imidazoline Receptors Type-2 (I2Rs)
Imidazoline receptors (IRs), also known as imidazoline binding sites, consist of two subtypes: I1R and I2R. Though the functions of type-2 imidazoline receptors are unknown, its contribution to various CNS disorders, such as AD, PD, HD, aging, depression, and glial cell tumors, is known. [11C]FTIMD (125), an I2R PET tracer, showed region-specific binding in rat and monkey brains. However, the binding specificity was relatively low.(448,449) The [11C]BU99008 (126) PET radiotracer for I2R imaging showed high specific binding and brain penetration in porcine and rhesus monkey brain.(450,451) Currently, [11C]BU99008 PET imaging is under human clinical trial in Alzheimer’s and healthy control patients, where the preliminary studies have shown quite promising results.(452)
5.6. Monoamine Oxidase Enzyme
MAO enzyme has two subtypes, MAO-A and MAO-B, where MAO-B showed upregulation in the neuroinflammation of AD.(453) MAO-B radioligand [11C]DED (l-[11C]deprenyl-D2) (127) PET imaging studies have been performed under various neuroinflammatory conditions involving astrogliosis, such as AD(454) and ALS(455) Though studies of MAO-B PET imaging reported knowledge on astrocyte function, its expression is also observed in serotonergic and histaminergic neurons;(456) hence, the results need to be cautiously evaluated.
5.7. Cyclooxygenase (COX)
The COX-1 and COX-2 are involved in catalyzing the conversion of arachidonic acid to prostaglandin, involved in inflammatory signaling. The [11C]ketoprofen ([11C]KTP) (128) PET tracer provided the usefulness of COX-1 in a rodent study.(457) Other studies showed microglial selectivity following the injection of inflammatory agents.(458) Another radiotracer [11C]KTP-ME (129) (COX-1 radioligand) is ready for human studies.
5.8. Arachidonic Acid
It is considered as a potential imaging target for neuroinflammation, despite its nonspecific cellular localization, as it plays an important role in the neuroinflammation process.(459) Involvement of this acid metabolism was studied in the brains of AD patients, along with visual stimulation, and its involvement in neurotransmission with [11C]arachidonic acid (130) imaging studies.
5.9. Adenosine Receptors
The A2A receptor’s (A2AR) involvement in neuroinflammatory processes has been studied in various human neurological disorders, including PD and schizophrenia. The higher A2AR binding in the activated microglia(460) was observed by using the [11C]TMSX (76) radioligand for imaging secondary progressive MS patients.(461) Studies using A2AR ligands are limited by specificity issues. To assess the pathological consequences of neuroinflammation, [11C]PIB (107) PET imaging reported for Aβ plaques in human subjects has also been used to assess demyelination.(462)[11C]Flumazenil (3) radioligand targeting GABAA receptors have been used to image neuronal integrity in neurological disorders such as stroke(463) and AD(464) (Figure 10).
Figure 10
Figure 10. List of various target-specific carbon-11 radiotracers for neuroinflammation.
6. Conclusion
ARTICLE SECTIONS
Based on recent findings on various receptor targets, enzymes, and pathways, the development of various carbon-11 radiotracers used as PET imaging agents and its intriguing application in oncology, cardiology, neurology, and neuroinflammation is at a promising stage. To date, various target receptors and pathways have been identified as potential biomarkers for tumor diagnosis, prognosis, and therapy. Their application in PET imaging has been elaborated in this review with emphasis on receptor tyrosine kinases, tyrosine kinase inhibitors, membrane phospholipid phosphatidylcholine, DNA synthesis measurement, and several amino acid transporters.
In cardiology, the identified biological processes and target receptors for PET imaging include oxidative metabolism for quantification of myocardial blood flow and determination of oxygen consumption; fatty acid metabolism for ischemia; beta-adrenoreceptors which act as a hallmark of cardiac failure besides being applied in idiopathic dilated cardiomyopathies study; presynaptic sympathetic innervation explored in ischemia, heart failure and arrhythmia, and angiotensin II type 1 receptors in myocardial infarction; and cannabinoid type 1 receptors in atherosclerosis, cardiac dysfunction, and CAD. Various molecular targets have been reported in brain imaging with a focus on their applications under normal, abnormal, and diseased conditions. This review has summarized the role of these receptors, enzymes, and pathways along with its contribution in the development and enhancement of various widespread neurodegenerative and neurological disorders, such as AD, PD, HD, MS, ALS, cerebral ischemia, neuropathic pain, temporal lobe epilepsy with detailed explanation on DATs, dopamine receptors, VMAT2, adenosine receptors, PD10, SV2A, glutamatergic receptors, opiate receptors, GABA receptors, serotonergic receptors -5HT1A5HT2A, SERTs, nicotinic receptors, muscarinic receptors, AChE, beta-amyloid, tau, kynurenine pathway, and NMDA receptors along with several specific carbon-11-labeled radioligands. For various neuropsychiatric and neurobehavioral disorders including depression, schizophrenia, bipolar disorder, autism, cognitive impairment, ADHD, the value of DAT, opiate, serotonergic and NMDA receptors have been widely explored. In alcoholics, smokers, and cocaine and other substance abusers, the importance of the change in density of receptors and changes in enzymes have shown interesting results by the utilization of several carbon-11 radiotracers as imaging agents.
Currently, neuroinflammation is a hot topic of research with increasing studies on the most commonly contributing receptor TSPO, along with recently explored alternative contributors such as GSK-3β, CB2 receptors, P2, I2R, MAO-B, COX-1, arachidonic acid, and adenosine receptors. This review provides collective information on the involvement of these receptor abnormalities and changes and how various target-specific carbon-11 PET radiopharmaceuticals provide valuable interpretation in several neurological illnesses such as AD, AD with dementia, MCI, PD, HD, FCD, FTD, corticobasal degeneration, ALS, PSP, epilepsy, HIV-associated dementia, stroke, and other CNS disorders. Besides this, the pathological consequences of neuroinflammation have also been monitored with stress on the BBB, demyelination, apoptosis, and neuronal loss considering molecular imaging agents against beta-amyloid, GABAA, and others.
This review is an approach to show the contribution of all of the extensive research on PET molecular targets, such as various physiological receptors, enzymes, pathways, and processes in normal as well as disease pathogenesis and how development and more discovery of certain target-specific carbon-11-labeled radioligands can be utilized widely in the diagnosis, disease progression, prediction, and therapy of some serious medical conditions covering tumors, neurodegenerative disorders, demyelinating diseases, addiction, neuropsychiatric illnesses, and neuroinflammatory conditions and related pathologies adding burden to both the physical and mental health of both the patient and the caregiver.
Author Information
ARTICLE SECTIONS
- Nerella Sridhar Goud - Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India;
http://orcid.org/0000-0002-0132-9516;
- Pardeep Kumar - Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India;http://orcid.org/0000-0002-1832-798X
N.S.G., A.B.: These authors contributed equally.
Biographies
ARTICLE SECTIONS
Nerella Sridhar Goud
Nerella Sridhar Goud received his Master’s degree in Pharmaceutical Chemistry from Kakatiya University in 2014 and Ph.D. degree from the National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, in 2019. Now working as a research associate of radiochemistry at NIMHANS. His research interests include small-molecule synthesis, SAR studies, radiolabeling studies, drug discovery and development for cancer, and neuro-related diseases. He has published more than 20 research and review articles in peer-reviewed scientific journals. He is an awardee of Genius book and India book record for successfully delivering a marathon nonstop 30 h lecture on the principles of pharmaceutical chemistry.
Ahana Bhattacharya
Ahana Bhattacharya obtained her Master’s degree in Life Sciences (2016) with a specialization in Cell and Molecular Biology from Presidency University, Kolkata. During her Master’s, she worked on the identification of a common food-borne rotavirus by the PCR method. She completed her MPhil in Neurosciences (2017–2019) from NIMHANS. There she worked on the analysis of age-related protein aggregates in the ENS and brainstem under the guidance of Professor Yasha TC in the Department of Neuropathology. She secured the first position and was awarded the gold medal during her MPhil and graduation program. Currently, she is working as a research scholar in the Department of NIIR at NIMHANS. Her research interest lies in neurosciences, neurodegenerative disorders, molecular imaging, oncology, neuropathology, stem cell therapy, and molecular biology.
Raman Kumar Joshi
Raman Kumar Joshi obtained his Bachelor’s degree in Science (2008) and Master’s degree in Nuclear Medicine from Panjab University in 2015. He worked as a nuclear medicine technologist with GE Healthcare for four years. He also worked in various centers for PET and SPECT imaging modalities and gained tremendous knowledge in the field. His excels at cyclotron operation and radiolabeling of F-18, Ga-68, N-13, and Tc-99m isotopes for imaging and Re-188 and Lu-177 for the therapy. He has been working as a radiochemist at NIMHANS since July 2017. He is the member of the NIMHANS radiation safety committee. His area of interest includes medical cyclotron, radiolabeling, and troubleshooting. He has more than five publications in national and international journals.
Chandana Nagaraj
Chandana Nagaraj received her Bachelor’s degree in Medicine (MBBS) from Bangalore Medical College in 2003 and Master’s degree in Medicine-DNB (Nuclear Medicine) from Christian Medical College in 2010. She has been an associate professor at NIMHANS since 2015. She is involved in many skill development programs and teaching for the paramedical staff, technologists, radiochemists, physicists, radiographers, and students with a view to enabling them to acquire skills and expertise for continued growth and excellence in research. Her research interest mainly focuses on PET image processing techniques, sequential analysis, pharmacokinetic modeling, etc. Currently, she is handling four major clinical research projects funded by different Indian government agencies like ICMR, DST, and NIMHANS.
Rose Dawn Bharath
Rose Dawn Bharath obtained her Bachelor’s degree in Medicine (MBBS) from Kempegowda Institute of Medical Sciences in 1999 and Master’s degree in Medicine-DNB from Manipal Hospital, Bangalore, in 2003. She has completed the Doctor of Medicine (DM) course from the National Institute of Mental Health & Neurosciences (NIMHANS) in 2007. Currently, she is a professor of neuroimaging and interventional radiology with 17 years of experience in imaging techniques and 14 years of exclusive neuroimaging expertise. Apart from being a consultant neuroradiologist, she has an active research interest in the field of functional neuroimaging and currently is in charge of the DST sponsored Advanced Brain Imaging Facility at NIMHANS. She has more than 200 publications in peer-reviewed scientific journals.
Pardeep Kumar
Pardeep Kumar has obtained his Ph.D. from Panjab University, Chandigarh, and did a thesis on the development of novel radiotracers for cancer detection at the Department of Nuclear Medicine, PGIMER, Chandigarh, from 2009 to 2013. Afterward, he joined as a postdoctoral fellow at Thomas Jefferson University, Philadelphia, PA, USA, under Prof. Mathew Thakur from 2013 to 2017. He has developed gallium-68-labeled peptide for the detection of breast cancer using micro PET-CT imaging. He has joined NIMHANS as an assistant professor of radiochemistry in the Department of NIIR in 2018. His research interest involves developing radiotracers for imaging neuro disorders, chemoresistance, and gliomas.
Acknowledgments
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The authors are thankful to the National Institute of Mental Health and Neuro-Sciences & Ministry of Health & Family Welfare, Govt. of India, for providing resources and support.
| Abbreviations Used | |
| AAs | amino acids |
| AADC | aromatic l-amino acid decarboxylase |
| AβPP | amyloid beta precursor protein |
| ACE | angiotensin-converting enzyme |
| AChE | acetylcholinesterase |
| AD | Alzheimer’s disease |
| ADHD | attention deficit hyperactivity disorder |
| AGE | advanced glycation end product |
| ALS | amyotrophic lateral sclerosis |
| APUD | amine precursor uptake and decarboxylation |
| AR | adenosine receptors |
| AT1-RC | angiotensin II receptor type 1 |
| BBB | blood–brain barrier |
| BD | bipolar disorder |
| BDZ | benzodiazepine |
| CA | carrier-added |
| CAD | coronary artery disease |
| cAMP | cyclic adenosine monophosphate |
| CB | cannabinoid receptor |
| CBD | corticobasal degeneration |
| CB1-R | cannabinoid type 1 receptor |
| cGMP | cyclic guanosine monophosphate |
| CNS | central nervous system |
| CO2 | carbon dioxide |
| COMT | catechol-O-methyltransferase |
| DA | dopamine |
| DATs | dopamine transporters |
| dMCAO | distal middle cerebral artery occlusion |
| DMSO–DMF | dimethyl sulfoxide–dimethylformamide |
| EGFR | epidermal growth factor receptor |
| EOB | end of bombardment |
| EOS | end of radiosynthesis |
| ERP | end of radionuclide production |
| FA | fatty acid |
| FFA | free fatty acid |
| FMAU | 2′-fluoro-5-methyl-1-β-d-arabino-furanosyluracil |
| FTD | frontotemporal dementia |
| GBq | gigabecquerel |
| GC | gas chromatography |
| HD | Huntington’s disease |
| HER2 | human epidermal growth factor receptor 2 |
| HGG | high-grade glioma |
| HPLC | high-performance liquid chromatography |
| 5-HTP | 5-hydroxytryptophan |
| IDO | indole amine 2,3-dioxygenase |
| LAH | lithium aluminum hydride |
| LAL | limulus amebocyte lysate |
| LAT | l-type amino acid transporter |
| LGG | low-grade glioma |
| mAChRs | muscarinic receptors |
| MAGL | monoacylglycerol lipase |
| MAO | monoamine oxidase |
| MAPK | mitogen-activated protein kinase |
| MBF | myocardial blood flow |
| MBq | megabecquerel |
| MCI | mild cognitive impairment |
| mCi | millicurie |
| MDD | major depressive disorder |
| mGluR | metabotropic glutamate receptor |
| MS | multiple sclerosis |
| MSNs | medium spiny neurons |
| nAChRs | nicotinic-cholinergic receptors |
| NCA | no-carrier-added |
| NE | norepinephrine |
| NET | NE reuptake transporter |
| NMDA | N-methyl-d-aspartate |
| NSCLC | non-small-cell lung carcinoma |
| PC | phosphatidylcholine |
| PD | Parkinson’s disease |
| PET | positron emission tomography |
| PFC | prefrontal cortex |
| PNS | peripheral nervous system |
| PSP | progressive supranuclear palsy |
| RT | room temperature |
| RTKs | receptor tyrosine kinase |
| SERT | serotonin transporter |
| TBAH | tetrabutylammonium hydroxide |
| TBR | tumor-to-background ratio |
| TCA | tricarboxylic acid |
| TEA | triethylamine |
| TK-1 | thymidine kinase-1 |
| TKI | tyrosine kinase inhibitors |
| TLC | thin layer chromatography |
| TLE | temporal lobe epilepsy |
| TMAO | trimethylamine N-oxide |
| TMP | thymidine monophosphate |
| TSPO | translocator protein |
| VEGF | vascular endothelial growth factor |
| VEGFR | vascular endothelial growth factor receptor |
| VMAT2 | vesicular monoamine transporter type 2 |
References
ARTICLE SECTIONS
This article references 464 other publications.
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- 3Goud, N. S.; Kanth Makani, V. K.; Pranay, J.; Alvala, R.; Qureshi, I. A.; Kumar, P.; Bharath, R. D.; Nagaraj, C.; Yerramsetty, S.; Pal-Bhadra, M.; Alvala, M. Synthesis, 18F- radiolabeling and apoptosis inducing studies of novel 4, 7-disubstituted coumarins. Bioorg. Chem. 2020, 97, 103663, DOI: 10.1016/j.bioorg.2020.103663[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjvVKgsr4%253D&md5=eb06c1662428a62783e8607c22290695Synthesis, 18F-radiolabeling and apoptosis inducing studies of novel 4,7-disubstituted coumarinsGoud, Nerella Sridhar; Kanth Makani, Venkata Krishna; Pranay, Jakkula; Alvala, Ravi; Qureshi, Insaf A.; Kumar, Pardeep; Bharath, Rose Dawn; Nagaraj, Chandana; Yerramsetty, Suresh; Pal-Bhadra, Manika; Alvala, MallikaBioorganic Chemistry (2020), 97 (), 103663CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)A new series of 4,7-disubstituted coumarin derivs. I [R1 = morpholin-4-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 4-methylpiperidin-1-yl, etc.; R2 = cyanomethyl, (4-methoxyphenyl)methyl, (4-bromophenyl)methyl, etc.] have been synthesized as galectin-1 targeting apoptosis inducing agents and evaluated for their in vitro cytotoxic potentials against a panel of selected human cancer cell lines namely, Brest (MCF7), Ovarian (SKOV3), Prostate (PC-3 & DU145) and normal embryonic kidney (HEK293T) cells, using MTT assay. Most of the compds. I exhibited potent growth inhibitory action against the treated cancer cell lines with an IC50 range of 10-30μM. Compd. I [R1 = 4-ethoxycarbonyl-piperidin-1-yl; R2 = (4-nitrophenyl)methyl (A)] exhibited a significant growth inhibition against prostate cancer (PC-3 & DU145) cell lines with an IC50 value of 7.45 ± 0.03μM, 8.95 ± 0.17μM resp. Further, the target compd. A was radiolabeled with fluorine-18 [18F] to be used as a novel PET radiotracer for imaging of tumors via targeting galectin-1, using appropriate reaction conditions in the GE Tracer-lab FX2N synthesis module. The purifn. of the [18F] radiolabeled compd. II was successfully achieved with 60% ethanol. The radiochem. purity was >85% and residual solvent limit of DMF was 65 ± 3 ppm as analyzed by HPLC, TLC & GC anal. methods. The apoptosis studies confirm the inhibition of cell proliferation with morphol. changes like cell shrinkage, blebbing and cell wall deformation, increasing the ROS levels, and loss of mitochondrial membrane potential by Acridine orange/Ethidium bromide staining, Hoechst-33342 staining, H2DCFDA staining, annexin V-FITC/PI, and JC-1 staining methods. In flow cytometric anal., the sub-G1 phase of the cell cycle is selectively arrested in a dose-dependent manner. In Gal-1 ELISA studies, compd. A efficiently reduced the levels of Gal-1 protein in dose-dependent manner with an IC50 value of 100μM. The binding const. (Ka) of A with Gal-1 was obsd. as 1.3 × 104 M-1 by fluorescence spectroscopy. The mol. docking studies clearly showed possible interactions and the pharmacokinetic (ADMET) properties of compd. A with Gal-1. The novel 4,7-disubstituted coumarins I could be a potential cytotoxic and PET imaging agents via Gal-1.
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- 9Kostakoglu, L.; Agress, H.; Goldsmith, S. J. Clinical role of FDG PET in evaluation of cancer patients. Radio Graphics. 2003, 23, 315– 340, DOI: 10.1148/rg.232025705
- 10Been, L. B.; Suurmeijer, A. J. H.; Cobben, D. C. P.; Jager, P. L.; Hoekstra, H. J.; Elsinga, P. H. [18F]FLT-PET in oncology: Current status and opportunities. Eur. J. Nucl. Med. Mol. Imaging 2004, 31, 1659– 1672, DOI: 10.1007/s00259-004-1687-6[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cngvVKrug%253D%253D&md5=749bd7572d93eed431023cd1041973bd18F]FLT-PET in oncology: current status and opportunitiesBeen Lukas B; Suurmeijer Albert J H; Cobben David C P; Jager Pieter L; Hoekstra Harald J; Elsinga Philip HEuropean journal of nuclear medicine and molecular imaging (2004), 31 (12), 1659-72 ISSN:1619-7070.In recent years, [18F]-fluoro-3'-deoxy-3'-L: -fluorothymidine ([18F]FLT) has been developed as a proliferation tracer. Imaging and measurement of proliferation with PET could provide us with a non-invasive staging tool and a tool to monitor the response to anticancer treatment. In this review, the basis of [18F]FLT as a proliferation tracer is discussed. Furthermore, an overview of the current status of [18F]FLT-PET research is given. The results of this research show that although [18F]FLT is a tracer that visualises cellular proliferation, it also has certain limitations. In comparison with the most widely used PET tracer, [18F]FDG, [18F]FLT uptake is lower in most cases. Furthermore, [18F]FLT uptake does not always reflect the tumour cell proliferation rate, for example during or shortly after certain chemotherapy regimens. The opportunities provided by, and the limitations of, [18F]FLT as a proliferation tracer are addressed in this review, and directions are given for further research, taking into account the strong and weak points of the new tracer.
- 11Richardson, M. P.; Koepp, M. J.; Brooks, D. J.; Duncan, J. S. 11C-flumazenil PET in neocortical epilepsy. Neurology 1998, 51, 485– 492, DOI: 10.1212/WNL.51.2.485[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXls1Wqtr0%253D&md5=76224abba31a5d69bbb6e8be42aedd4111C-flumazenil PET in neocortical epilepsyRichardson, M. P.; Koepp, M. J.; Brooks, D. J.; Duncan, J. S.Neurology (1998), 51 (2), 485-492CODEN: NEURAI; ISSN:0028-3878. (Lippincott-Raven Publishers)Objective: To investigate focal cortical abnormalities of γ-aminobutyric acid type A-central benzodiazepine receptors (GABAA-cBZRs) in patients with extratemporal partial seizures with acquired lesions and in patients with normal high-resoln. MRI. Methods: Six patients with acquired lesions and 18 patients with normal high-resoln. MRI and extratemporal partial seizures, as well as 24 normal controls, were studied with 11C-flumazenil (FMZ) PET to produce voxel-by-voxel images of FMZ vol. of distribution (FMZVD), which reflects d. of GABAA-cBZRs. These images were analyzed using Statistical Parametric Mapping (SPM). Each patient was compared with the control group to reveal regions with abnormal FMZVD at p < 0.001 uncorrected, cor. to p < 0.05 for the whole brain vol. Each normal control was compared with the remaining controls in the same manner. Results: All six patients with acquired lesions had a single region of reduced FMZVD. Thirteen of 18 patients with normal MRI had regions of abnormal cortical FMZVD: 10 had regions of increased FMZVD, 6 had regions of decreased FMZVD, and 3 had both regions of increased and decreased FMZVD. Seven patients had an abnormality in the lobe and 12 in the hemisphere of presumed seizure origin. Conclusions: FMZ PET analyzed with SPM is an automated, objective, sensitive, and specific means for detecting regional cortical abnormalities of GABAA-cBZRs in patients with partial seizures. This technique may be useful in the evaluation of patients with refractory partial seizures for surgical treatment, particularly in those patients with normal MRI.
- 12Hirvonen, J.; Aalto, S.; Lumme, V.; Någren, K.; Kajander, J.; Vilkman, H.; Hagelberg, N.; Oikonen, V.; Hietala, J. Measurement of striatal and thalamic dopamine D2 receptor binding with 11C-raclopride. Nucl. Med. Commun. 2003, 24, 1207– 1214, DOI: 10.1097/00006231-200312000-00002[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXptV2jt7c%253D&md5=2e36c9233157203fb37378d6a2efd8ecMeasurement of striatal and thalamic dopamine D2 receptor binding with 11C-racloprideHirvonen, J.; Aalto, S.; Lumme, V.; Nagren, K.; Kajander, J.; Vilkman, H.; Hagelberg, N.; Oikonen, V.; Hietala, J.Nuclear Medicine Communications (2003), 24 (12), 1207-1214CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)11C-Raclopride is a widely used positron emission tomog. (PET) tracer for measurement of striatal D2 dopamine receptor binding characteristics. Recently, 11C-raclopride has also been used for quantification of thalamic D2 receptor binding. We studied reproducibility and validity issues on the thalamic D2 binding measurements using healthy volunteer test-retest data and simulated data. Eight healthy male volunteers received 11C-raclopride as a bolus injection in a std. test-retest design using 3-dimensional PET. The displacement of thalamic 11C-raclopride binding by the D2 receptor antagonist haloperidol was studied in two female schizophrenic patients. With regards to reproducibility and reliability, thalamic 11C-raclopride binding could be described with a simplified ref. tissue model resulting in binding potentials (BPs) between 0.38 and 0.66. In comparison, the model failed to describe 11C-raclopride binding consistently in temporal cortex due to low specific signal. Measurement of thalamic 11C-raclopride BP was reproducible with a test-retest variability of 7.6±6.2% and reliable with an intraclass correlation coeff. (ICC) of 0.87. Comparable ICCs were obsd. in caudate and putamen (0.84-0.96). With regard to validity, subchronic low dose haloperidol treatment reduced specific 11C-raclopride binding equally in putamen and thalamus but a higher dose induced clearly higher D2 receptor occupancy in putamen than in thalamus. Noise simulations indicated that this can partly be explained by an over-estn. of thalamic D2 receptor BP in noisy conditions (low signal, high occupancy). The D2 receptor BP in putamen was clearly more resistant to noise. We conclude that the reproducibility and reliability of thalamic 11C-raclopride BP is good and equal to, or only slightly less than, those obsd. in caudate or putamen. However, the signal-to-noise ratio for quantification may become too low esp. in receptor occupancy-type studies, leading to an artifactual underestimation of measured D2 receptor occupancy.
- 13Glaudemans, A. W. J. M.; Enting, R. H.; Heesters, M. A. A. M.; Dierckx, R. A. J. O.; van Rheenen, R. W. J.; Walenkamp, A. M. E.; Slart, R. H. J. A. Value of 11C-methionine PET in imaging brain tumours and metastases. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 615– 635, DOI: 10.1007/s00259-012-2295-5[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjslOgsbs%253D&md5=2167374e019d48fc0b10ac25625074d3Value of 11C-methionine PET in imaging brain tumours and metastasesGlaudemans, Andor W. J. M.; Enting, Roelien H.; Heesters, Mart A. A. M.; Dierckx, Rudi A. J. O.; Rheenen, Ronald W. J.; Walenkamp, Annemiek M. E.; Slart, Riemer H. J. A.European Journal of Nuclear Medicine and Molecular Imaging (2013), 40 (4), 615-635CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. 11C-methionine (MET) is the most popular amino acid tracer used in PET imaging of brain tumors. Because of its characteristics, MET PET provides a high detection rate of brain tumors and good lesion delineation. This review focuses on the role of MET PET in imaging cerebral gliomas. The Introduction provides a clin. overview of what is important in primary brain tumors, recurrent brain tumors and brain metastases. The indications for radiotherapy and the results and problems arising after chemoradiotherapy in relation to imaging (pseudoprogression or radionecrosis) are discussed. The working mechanism, scan interpretation and quantification possibilities of MET PET are then explained. A literature overview is given of the role of MET PET in primary gliomas (diagnostic accuracy, grading, prognosis, assessment of tumor extent, biopsy and radiotherapy planning), in brain metastases, and in the differentiation between tumor recurrence and radiation necrosis. Finally, MET PET is compared to other nuclear imaging possibilities in brain tumor imaging.
- 14Welle, C. L.; Cullen, E. L.; Peller, P. J.; Lowe, V. J.; Murphy, R. C.; Johnson, G. B.; Binkovitz, L. A. 11 C-Choline PET/CT in recurrent prostate cancer and nonprostatic neoplastic processes. Radio Graphics. 2016, 36, 279– 292, DOI: 10.1148/rg.2016150135
- 15Sridhar Goud, N.; Pooladanda, V.; Muni Chandra, K.; Lakshmi Soukya, P. S.; Alvala, R.; Kumar, P.; Nagaraj, C.; Dawn Bharath, R.; Qureshi, I. A.; Godugu, C.; Alvala, M. Novel benzimidazole-triazole hybrids as apoptosis inducing agents in lung cancer: Design, synthesis, 18F-radiolabeling & galectin-1 inhibition studies. Bioorg. Chem. 2020, 102, 104125, DOI: 10.1016/j.bioorg.2020.104125[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFWju7nE&md5=ab2951bd894bb4089cac3982d7980c87Novel benzimidazole-triazole hybrids as apoptosis inducing agents in lung cancer: Design, synthesis, 18F-radiolabeling & galectin-1 inhibition studiesSridhar Goud, Nerella; Pooladanda, Venkatesh; Muni Chandra, K.; Lakshmi Soukya, P. S.; Alvala, Ravi; Kumar, Pardeep; Nagaraj, Chandana; Dawn Bharath, Rose; Qureshi, Insaf A.; Godugu, Chandraiah; Alvala, MallikaBioorganic Chemistry (2020), 102 (), 104125CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)A new series of benzimidazole-triazole hybrids I [R = Ph, benzyl, 1-naphthyl, etc.] as galectin-1 (gal-1) mediated apoptosis-inducing agents were synthesized and evaluated for their potential anticancer activity against a panel of human cancer cell lines viz. breast cancer (MCF-7 and MDA-MB-231), lung cancer (A-549 and NCI-H460), and human keratinocyte cancer (HaCaT) using MTT assay. The target compd. I [R = 3-hydroxyphenyl] exhibited an excellent growth inhibition against lung cancer (A-549 and NCI-H460) cells with an IC50 value of 0.63 ± 0.21μM, and 0.99 ± 0.01μM resp. The target compd. I [R = 3-hydroxyphenyl] also showed a significant growth inhibition against breast cancer (MCF-7 and MDA-MB-23) with an IC50 value of 1.3 ± 0.18μM, and 0.94 ± 0.02μM resp. In addn., the radiochem. synthesis was performed using fluorine-18 radionuclide in the GE Tracer-lab FX2N module to prove the target compd. I [R = 3-hydroxyphenyl] as a PET imaging agent. In the final stage, the 18F-I [R = 3-hydroxyphenyl] target compd. was successfully purified with 60% ethanol in water. The radiochem. purity was achieved >95% using HPLC and the residual solvent DMF limit was around 78 ± 3 ppm confirmed by GC anal. Further, the apoptosis induction by I [R = 3-hydroxyphenyl] in lung cancer (A-549) cells was confirmed as a result of the decrease in MMP levels, increased percentage of apoptotic cells and sub G1 phase arrest by JC-1 staining, DAPI staining, annexin V-FITC/PI and flow cytometric anal. In addn., the target compd. I [R = 3-hydroxyphenyl] significantly reduced the gal-1 protein levels in a dose-dependent manner as confirmed by ELISA studies. The protein binding studies like Surface Plasmon Resonance (SPR) and Fluorescence Spectroscopy (FS) studies indicated that the target compd. I [R = 3-hydroxyphenyl] is capable of binding to gal-1 with an equil. const. (KD) value of 1.19E-06 M and binding const. (Ka) of 9.5 x 103 M-1 resp. The in-silico computational studies also revealed possible interactions and pharmacokinetic properties (ADMET) of compd. I [R = 3-hydroxyphenyl] with the binding domain of gal-1. Therefore, the novel benzimidazole-triazole hybrids I as apoptosis-inducing agents in lung cancer would be potential cytotoxic and PET imaging agents via gal-1.
- 16Tu, Z.; Mach, R. H. C-11 radiochemistry in cancer imaging applications. Curr. Top. Med. Chem. 2010, 10, 1060– 1095, DOI: 10.2174/156802610791384261[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovFaqs7o%253D&md5=75c9b8aedd01b1f8b7917c30c77f6e63C-11 radiochemistry in cancer imaging applicationsTu, Z.; Mach, R. H.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (11), 1060-1095CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. Carbon-11 (C-11) radiotracers are widely used for the early diagnosis of cancer, monitoring therapeutic response to cancer treatment, and pharmacokinetic investigations of anticancer drugs. PET imaging permits non-invasive monitoring of metabolic processes and mol. targets, while carbon-11 radiotracers allow a "hot for cold" substitution of biol. active mols. Advances in org. synthetic chem. and radiochem. as well as improved automated techniques for radiosynthesis have encouraged investigators in developing carbon-11 tracers for use in oncol. imaging studies. The short half-life of carbon-11 (20.38 min) creates special challenges for the synthesis of C-11 labeled tracers; these include the challenges of synthesizing C-11 target compds. with high radiochem. yield, high radiochem. purity and high specific activity in a short time and on a very small scale. The optimization of conditions for making a carbon-11 tracer include the late introduction of the C-11 isotope, the rapid formation and purifn. of the target compd., and the use of automated systems to afford a high yield of the target compd. in a short time. In this review paper, we first briefly introduce some basic principles of PET imaging of cancer; we then discuss principles of carbon-11 radiochem., focus on specific advances in radiochem., and describe the synthesis of C-11 radiopharmaceuticals developed for cancer imaging. The carbon-11 radiochem. approaches described include the N,O, and S-alkylations of [11C]methyl iodide/[11C]methyl triflate and analogs of [11C]methyl iodide and their applications for making carbon-11 tracers; we then address recent advances in exploring a transmetallic complex mediated [11C]carbonyl reaction for oncol. targets.
- 17Andersson, J.; Truong, P.; Halldin, C. In-target produced [11C]methane: Increased specific radioactivity. Appl. Radiat. Isot. 2009, 67, 106– 110, DOI: 10.1016/j.apradiso.2008.09.010[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjmsVWqtw%253D%253D&md5=33616267a39cd427186f4e2995fa723eIn-target produced [11C]methane: Increased specific radioactivityAndersson Jan; Truong Phong; Halldin ChristerApplied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine (2009), 67 (1), 106-10 ISSN:.The (14)N(rho, alpha)(11)C reaction on N(2)-O(2) or N(2)-H(2) gaseous systems as targets in proton bombardment allows for the production of [(11)C]CO(2) and [(11)C]CH(4.) We report the target production of [(11)C]CH(4) and the gas phase iodination to produce [(11)C]CH(3)I with high specific radioactivity (SA). SA was calculated for four different radiopharmaceuticals produced in-house from both target produced [(11)C]CO(2) and [(11)C]CH(4.) For [(11)C]raclopride we obtained an average SA of 3908 GBq/mumol (106000 Ci/mmol) at the end of bombardment for the last 52 productions, which is a 32-fold increase compared to when using the in-house [(11)C]CO(2) target.
- 18Hara, T.; Iio, M. On-line synthesis of [11C]cyanide from cyclotron-produced [11C]carbon dioxide. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1987, 38, 1092– 1093, DOI: 10.1016/0883-2889(87)90077-3
- 19Coenen, H. H.; Gee, A. D.; Adam, M.; Antoni, G.; Cutler, C. S.; Fujibayashi, Y.; Jeong, J. M.; Mach, R. H.; Mindt, T. L.; Pike, V. W.; Windhorst, A. D. Consensus nomenclature rules for radiopharmaceutical chemistry — Setting the record straight. Nucl. Med. Biol. 2017, 55, v– xi, DOI: 10.1016/j.nucmedbio.2017.09.004
- 20Pike, V. W. PET Radiotracers: Crossing the blood–brain barrier and surviving metabolism. Trends Pharmacol. Sci. 2009, 30, 431– 440, DOI: 10.1016/j.tips.2009.05.005[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpt1KgsLg%253D&md5=97704995fecd968baf1e0892bf70324ePET radiotracers: crossing the blood-brain barrier and surviving metabolismPike, Victor W.Trends in Pharmacological Sciences (2009), 30 (8), 431-440CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)A review. Radiotracers for imaging protein targets in the living human brain with positron emission tomog. (PET) are increasingly useful in clin. research and in drug development. Such radiotracers must fulfill many criteria, among which an ability to enter brain adequately and reversibly without contamination by troublesome radiometabolites is desirable for accurate measurement of the d. of a target protein (e.g. neuroreceptor, transporter, enzyme or plaque). Candidate radiotracers can fail as a result of poor passive brain entry, rejection from brain by efflux transporters or undesirable metab. These issues are reviewed. Emerging PET radiotracers for measuring efflux transporter function and new strategies for ameliorating radiotracer metab. are discussed. A growing understanding of the mol. features affecting the brain penetration, metab. and efflux transporter sensitivity of prospective radiotracers should ultimately lead to their more rational and efficient design, and also to their greater efficacy.
- 21Synowiecki, M. A.; Perk, L. R.; Nijsen, J. F. W. Production of novel diagnostic radionuclides in small medical cyclotrons. EJNMMI Radiopharmacy and Chemistry. 2018, 3, 3, DOI: 10.1186/s41181-018-0038-z[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mrns1Wjtg%253D%253D&md5=44e838388dca94875af39bd0ce3679e7Production of novel diagnostic radionuclides in small medical cyclotronsSynowiecki Mateusz Adam; Perk Lars Rutger; Nijsen J Frank WEJNMMI radiopharmacy and chemistry (2018), 3 (1), 3 ISSN:.The global network of cyclotrons has expanded rapidly over the last decade. The bulk of its industrial potential is composed of small medical cyclotrons with a proton energy below 20 MeV for radionuclides production. This review focuses on the recent developments of novel medical radionuclides produced by cyclotrons in the energy range of 3 MeV to 20 MeV. The production of the following medical radionuclides will be described based on available literature sources: Tc-99 m, I-123, I-124, Zr-89, Cu-64, Ga-67, Ga-68, In-111, Y-86 and Sc-44. Remarkable developments in the production process have been observed in only some cases. More research is needed to make novel radionuclide cyclotron production available for the medical industry.
- 22Funk, T.; Sun, M.; Hasegawa, B. H. Radiation dose estimate in small animal SPECT and PET. Med. Phys. 2004, 31, 2680– 2686, DOI: 10.1118/1.1781553[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnsVChsrw%253D&md5=eb10ef8e6140565e4b85e5324e39823cRadiation dose estimate in small animal SPECT and PETFunk, Tobias; Sun, Mingshan; Hasegawa, Bruce H.Medical Physics (2004), 31 (9), 2680-2686CODEN: MPHYA6; ISSN:0094-2405. (American Institute of Physics)Calcns. of radiation dose are important in assessing the medical and biol. implications of ionizing radiation in medical imaging techniques such as SPECT and PET. In contrast, radiation dose ests. of SPECT and PET imaging of small animals are not very well established. For that reason we have estd. the whole-body radiation dose to mice and rats for isotopes such as 18F, 99mTc, 201Tl, 111In, 123I, and 125I that are used commonly for small animal imaging. We have approximated mouse and rat bodies with uniform soft tissue equiv. ellipsoids. The mouse and rat sized ellipsoids had a mass of 30 g and 300 g, resp., and a ratio of the principal axes of 1:1:4 and 0.7:1:4. The absorbed fractions for various photon energies have been calcd. using the Monte Carlo software package MCNP. Using these values, we then calcd. MIRD S-values for two geometries that model the distribution of activity in the animal body: (a) a central point source and (b) a homogeneously distributed source, and compared these values against S-value calcns. for small ellipsoids tabulated in MIRD Pamphlet 8 to validate our results. Finally we calcd. the radiation dose taking into account the biol. half-life of the radiopharmaceuticals and the amt. of activity administered. Our calcns. produced S-values between 1.06×10-13 Gy/Bq s and 2.77×10-13 Gy/Bq s for SPECT agents, and 15.0×10-13 Gy/Bq s for the PET agent 18F, assuming mouse sized ellipsoids with uniform source distribution. The S-values for a central point source in an ellipsoid are about 10% higher than the values obtained for the uniform source distribution. Furthermore, the S-values for mouse sized ellipsoids are approx. 10 times higher than for the rat sized ellipsoids reflecting the difference in mass. We reviewed published data to obtain administered radioactivity and residence times for small animal imaging. From these values and our computed S-values we estd. that the whole body dose in small animals ranges between 6 cGy and 90 cGy for mice and between about 1 cGy and 27 cGy for rats. The whole body dose in small animal imaging can be very high in comparison to the LD to mice (LD50/30≈7 Gy). For this reason the dose in small animal imaging should be monitored carefully and the administered activity should be kept to a min. These results also underscore the need of further development of instrumentation that improves detection efficiency and reduces radiation dose in small animal imaging.
- 23Dong, F.; Du, J.; Miao, C.; Jia, L.; Li, W.; Wang, M.; Zheng, Q.-H.; Xu, Z. Radiosynthesis of carbon-11 labeled PDE5 inhibitors as new potential PET radiotracers for imaging of Alzheimer’s disease. Appl. Radiat. Isot. 2019, 154, 108873, DOI: 10.1016/j.apradiso.2019.108873[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1GktL7M&md5=c30f25f6570a5233a5343c4efb19c163Radiosynthesis of carbon-11 labeled PDE5 inhibitors as new potential PET radiotracers for imaging of Alzheimer's diseaseDong, Fugui; Du, Jie; Miao, Caihong; Jia, Limeng; Li, Wei; Wang, Min; Zheng, Qi-Huang; Xu, ZhidongApplied Radiation and Isotopes (2019), 154 (), 108873CODEN: ARISEF; ISSN:0969-8043. (Elsevier Ltd.)To develop PET tracers for imaging of Alzheimer's disease, new carbon-11 labeled potent and selective PDE5 inhibitors have been synthesized. The ref. stds. (5) and (12), and their corresponding desmethylated precursors (6) and (13) were synthesized from Me 2-amino-5-bromobenzoate and (4-methoxyphenyl)methanamine in multiple steps with 2%, 1%, 1% and 0.2% overall chem. yield, resp. The radiotracers ([11C]5) and ([11C]12) were prepd. from their corresponding precursors 6 and 13 with [11C]CH3OTf through O-11C-methylation and isolated by HPLC combined with SPE in 40-50% radiochem. yield, based on [11C]CO2 and decay cor. to EOB. The radiochem. purity was >99%, and the molar activity (Am) at EOB was in a range of 370-740 GBq/μmol.
- 24Gillings, N.; Todde, S.; Behe, M.; Decristoforo, C.; Elsinga, P.; Ferrari, V.; Hjelstuen, O.; Peitl, P. K.; Koziorowski, J.; Laverman, P.; Mindt, T. L.; Ocak, M.; Patt, M. EANM guideline on the validation of analytical methods for radiopharmaceuticals. EJNMMI Radiopharmacy and Chemistry. 2020, 5, 7, DOI: 10.1186/s41181-019-0086-z[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB387hsFamsA%253D%253D&md5=7314214c730ee0cf30686a6ddf9d3fd7EANM guideline on the validation of analytical methods for radiopharmaceuticalsGillings Nic; Todde Sergio; Behe Martin; Decristoforo Clemens; Elsinga Philip; Ferrari Valentina; Hjelstuen Olaug; Peitl Petra Kolenc; Koziorowski Jacek; Laverman Peter; Mindt Thomas L; Ocak Meltem; Patt MarianneEJNMMI radiopharmacy and chemistry (2020), 5 (1), 7 ISSN:.BACKGROUND: To fulfil good manufacturing requirements, analytical methods for the analysis of pharmaceuticals for human and vetinary use must be validated. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has published guidance documents on the requirements for such validation activities and these have been adopted by the European Medicines Agency, The U.S. Food and Drug Administration (FDA) and other regulatory bodies. These guidance documents do not, however, fully address all the specific tests required for the analysis of radiopharmaceuticals. This guideline attempts to rectify this shortcoming, by recommending approaches to validate such methods. RESULTS: Recommedations for the validation of analytical methods which are specific for radiopharmaceutials are presented in this guideline, along with two practical examples. CONCLUSIONS: In order to comply with good manufacturing practice, analytical methods for radiopharmaceuticals for human use should be validated.
- 25Li, S.; Schmitz, A.; Lee, H.; Mach, R. H. Automation of the radiosynthesis of six different 18F-labeled radiotracers on the allinone. EJNMMI Radiopharmacy and Chemistry. 2017, 1, 15, DOI: 10.1186/s41181-016-0018-0[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mnjs1egug%253D%253D&md5=bec3c23b749ff45e1056e5801c2adaa5Automation of the Radiosynthesis of Six Different (18)F-labeled radiotracers on the AllinOneLi Shihong; Schmitz Alexander; Lee Hsiaoju; Mach Robert HEJNMMI radiopharmacy and chemistry (2017), 1 (1), 15 ISSN:.Background: Fast implementation of positron emission tomography (PET) into clinical and preclinical studies highly demands automated synthesis for the preparation of PET radiopharmaceuticals in a safe and reproducible manner. The aim of this study was to develop automated synthesis methods for these six (18)F-labeled radiopharmaceuticals produced on a routine basis at the University of Pennsylvania using the AllinOne synthesis module. Results: The development of automated syntheses with varying complexity was accomplished including HPLC purification, SPE procedures and final formulation with sterile filtration. The six radiopharmaceuticals were obtained in high yield and high specific activity with full automation on the AllinOne synthesis module under current good manufacturing practice (cGMP) guidelines. Conclusion: The study demonstrates the versatility of this synthesis module for the preparation of a wide variety of (18)F-labeled radiopharmaceuticals for PET imaging studies.
- 26Mehmood, Y. What Is Limulus Amebocyte Lysate (LAL) and Its Applicability in Endotoxin Quantification of Pharma Products. In Growing and Handling of Bacterial Cultures; Mishra, M., Ed.; IntechOpen: 2019.
- 27Tu, Z.; Mach, R. H. C-11 radiochemistry in cancer imaging applications. Curr. Top. Med. Chem. 2010, 10, 1060– 1095, DOI: 10.2174/156802610791384261[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovFaqs7o%253D&md5=75c9b8aedd01b1f8b7917c30c77f6e63C-11 radiochemistry in cancer imaging applicationsTu, Z.; Mach, R. H.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (11), 1060-1095CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. Carbon-11 (C-11) radiotracers are widely used for the early diagnosis of cancer, monitoring therapeutic response to cancer treatment, and pharmacokinetic investigations of anticancer drugs. PET imaging permits non-invasive monitoring of metabolic processes and mol. targets, while carbon-11 radiotracers allow a "hot for cold" substitution of biol. active mols. Advances in org. synthetic chem. and radiochem. as well as improved automated techniques for radiosynthesis have encouraged investigators in developing carbon-11 tracers for use in oncol. imaging studies. The short half-life of carbon-11 (20.38 min) creates special challenges for the synthesis of C-11 labeled tracers; these include the challenges of synthesizing C-11 target compds. with high radiochem. yield, high radiochem. purity and high specific activity in a short time and on a very small scale. The optimization of conditions for making a carbon-11 tracer include the late introduction of the C-11 isotope, the rapid formation and purifn. of the target compd., and the use of automated systems to afford a high yield of the target compd. in a short time. In this review paper, we first briefly introduce some basic principles of PET imaging of cancer; we then discuss principles of carbon-11 radiochem., focus on specific advances in radiochem., and describe the synthesis of C-11 radiopharmaceuticals developed for cancer imaging. The carbon-11 radiochem. approaches described include the N,O, and S-alkylations of [11C]methyl iodide/[11C]methyl triflate and analogs of [11C]methyl iodide and their applications for making carbon-11 tracers; we then address recent advances in exploring a transmetallic complex mediated [11C]carbonyl reaction for oncol. targets.
- 28Luurtsema, G.; Verbeek, J.; Lubberink, M.; Lammertsma, A. A.; Dierckx, R.; Elsinga, P.; Windhorst, A. D.; van Waarde, A. Carbon-11 labeled tracers for in vivo imaging of P- glycoprotein function: Kinetics, advantages and disadvantages. Curr. Top. Med. Chem. 2010, 10, 1820– 1833, DOI: 10.2174/156802610792928013[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cfkslKnsw%253D%253D&md5=ccf0b321e7329db173e793590542075aCarbon-11 labeled tracers for in vivo imaging P-glycoprotein function: kinetics, advantages and disadvantagesLuurtsema G; Verbeek G L; Lubberink M; Lammertsma A A; Dierckx R; Elsinga P; Windhorst A D; van Waarde ACurrent topics in medicinal chemistry (2010), 10 (17), 1820-33 ISSN:.P-glycoprotein (P-gp) is a drug efflux transporter with broad substrate specificity localized in the blood-brain barrier and in several peripheral organs. In order to understand the role of P-gp in physiological and patho-physiological conditions, several carbon-11 labelled P-gp tracers have been developed and validated. This review provides an overview of the spectrum of radiopharmaceuticals that is available for this purpose. A short overview of the physiology of the blood-brain barrier in health and disease is also provided. Tracer kinetic modelling for quantitative analysis of P-gp function and expression is highlighted, and the advantages and disadvantages of the various tracers are discussed.
- 29Dahl, K.; Halldin, C.; Schou, M. New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals. Clinical and Translational Imaging. 2017, 5, 275– 289, DOI: 10.1007/s40336-017-0223-1[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnmsFGmtg%253D%253D&md5=35efea104c0af2ef8e9b45c4826a47b5New methodologies for the preparation of carbon-11 labeled radiopharmaceuticalsDahl Kenneth; Halldin Christer; Schou Magnus; Schou MagnusClinical and translational imaging (2017), 5 (3), 275-289 ISSN:2281-5872.PURPOSE: This short review aims to cover the more recent and promising developments of carbon-11 ((11)C) labeling radiochemistry and its utility in the production of novel radiopharmaceuticals, with special emphasis on methods that have the greatest potential to be translated for clinical positron emission tomography (PET) imaging. METHODS: A survey of the literature was undertaken to identify articles focusing on methodological development in (11)C chemistry and their use within novel radiopharmaceutical preparation. However, since (11)C-labeling chemistry is such a narrow field of research, no systematic literature search was therefore feasible. The survey was further restricted to a specific timeframe (2000-2016) and articles in English. RESULTS: From the literature, it is clear that the majority of (11)C-labeled radiopharmaceuticals prepared for clinical PET studies have been radiolabeled using the standard heteroatom methylation reaction. However, a number of methodologies have been developed in recent years, both from a technical and chemical point of view. Amongst these, two protocols may have the greatest potential to be widely adapted for the preparation of (11)C-radiopharmaceuticals in a clinical setting. First, a novel method for the direct formation of (11)C-labeled carbonyl groups, where organic bases are utilized as [(11)C]carbon dioxide-fixation agents. The second method of clinical importance is a low-pressure (11)C-carbonylation technique that utilizes solvable xenon gas to effectively transfer and react [(11)C]carbon monoxide in a sealed reaction vessel. Both methods appear to be general and provide simple paths to (11)C-labeled products. CONCLUSION: Radiochemistry is the foundation of PET imaging which relies on the administration of a radiopharmaceutical. The demand for new radiopharmaceuticals for clinical PET imaging is increasing, and (11)C-radiopharmaceuticals are especially important within clinical research and drug development. This review gives a comprehensive overview of the most noteworthy (11)C-labeling methods with clinical relevance to the field of PET radiochemistry.
- 30Rami-Mark, C.; Ungersboeck, J.; Haeusler, D.; Nics, L.; Philippe, C.; Mitterhauser, M.; Willeit, M.; Lanzenberger, R.; Karanikas, G.; Wadsak, W. Reliable set-up for in-loop 11C- carboxylations using Grignard reactions for the preparation of [carbonyl-11C]WAY- 100635 and [11C]-(+)-PHNO. Appl. Radiat. Isot. 2013, 82, 75– 80, DOI: 10.1016/j.apradiso.2013.07.023[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslKqsbbF&md5=f0c93e325715abc0db09121bfe7ecb05Reliable set-up for in-loop 11C-carboxylations using Grignard reactions for the preparation of [carbonyl-11C]WAY-100635 and [11C]-(+)-PHNORami-Mark, Christina; Ungersboeck, Johanna; Haeusler, Daniela; Nics, Lukas; Philippe, Cecile; Mitterhauser, Markus; Willeit, Matthaeus; Lanzenberger, Rupert; Karanikas, Georgios; Wadsak, WolfgangApplied Radiation and Isotopes (2013), 82 (), 75-80CODEN: ARISEF; ISSN:0969-8043. (Elsevier Ltd.)Aim of this work was the implementation of a generalized in-loop synthesis for 11C-carboxylations and subsequent 11C-acylations on the TRACERlab FxC Pro platform. The set-up was tested using [carbonyl-11C]WAY-100635 and, for the first time, [11C]-(+)-PHNO. Its general applicability could be demonstrated and both [carbonyl-11C]WAY-100635 and [11C]-(+)-PHNO were prepd. with high reliability and satisfying outcome.
- 31Rotstein, B. H.; Liang, S. H.; Holland, J. P.; Collier, T. L.; Hooker, J. M.; Wilson, A. A.; Vasdev, N. 11CO2 fixation: A renaissance in PET radiochemistry. Chem. Commun. 2013, 49, 5621, DOI: 10.1039/c3cc42236d[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosVemsbo%253D&md5=555cd1c94c0e870cf268ff5db0578c0c11CO2 fixation: a renaissance in PET radiochemistryRotstein, Benjamin H.; Liang, Steven H.; Holland, Jason P.; Collier, Thomas Lee; Hooker, Jacob M.; Wilson, Alan A.; Vasdev, NeilChemical Communications (Cambridge, United Kingdom) (2013), 49 (50), 5621-5629CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Carbon-11 labeled carbon dioxide is the cyclotron-generated feedstock reagent for most positron emission tomog. (PET) tracers using this radionuclide. Most carbon-11 labels, however, are installed using deriv. reagents generated from [11C]CO2. In recent years, [11C]CO2 has seen a revival in applications for the direct incorporation of carbon-11 into functional groups such as ureas, carbamates, oxazolidinones, carboxylic acids, esters, and amides. This review summarizes classical [11C]CO2 fixation strategies using organometallic reagents and then focuses on newly developed methods that employ strong org. bases to reversibly capture [11C]CO2 into soln., thereby enabling highly functionalized labeled compds. to be prepd. Labeled compds. and radiopharmaceuticals that have been translated to the clinic are highlighted.
- 32Hooker, J. M.; Reibel, A. T.; Hill, S. M.; Schueller, M. J.; Fowler, J. S. One-pot, direct incorporation of [11C]CO2 into carbamates. Angew. Chem., Int. Ed. 2009, 48, 3482– 3485, DOI: 10.1002/anie.200900112[Crossref], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXltFGhsL8%253D&md5=3710164e039643639811d7999396229dOne-Pot, Direct Incorporation of [11C]CO2 into CarbamatesHooker, Jacob M.; Reibel, Achim T.; Hill, Sidney M.; Schueller, Michael J.; Fowler, Joanna S.Angewandte Chemie, International Edition (2009), 48 (19), 3482-3485, S3482/1-S3482/10CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An operationally simple and mild reaction based on the direct fixation of 11CO2 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) has been developed for the synthesis of 11C-labeled carbamates at 75 °C within 10 min in radiochem. yields above 70 % (see scheme). This strategy should be immediately useful for the construction of new radiotracers for positron emission tomog. and other applications.
- 33Wilson, A. A.; Garcia, A.; Houle, S.; Vasdev, N. Direct fixation of [11C]-CO2 by amines: Formation of [11C-carbonyl]-methylcarbamates. Org. Biomol. Chem. 2010, 8, 428– 432, DOI: 10.1039/B916419G[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1Sqs7nK&md5=9d718725aeb709e694b43db9c4d0edb9Direct fixation of [11C]-CO2 by amines: formation of [11C-carbonyl]-methylcarbamatesWilson, Alan A.; Garcia, Armando; Houle, Sylvain; Vasdev, NeilOrganic & Biomolecular Chemistry (2010), 8 (2), 428-432CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)[11C-Carbonyl]-methylcarbamates can be synthesized directly from [11C]-CO2 and primary or secondary amines in a one-pot, two-step reaction. The use of either diazabicyclo[5.4.0]undec-7-ene (DBU) or 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) enables efficient trapping of [11C]-CO2 in small vols. of DMF as [11C]-carbamate salts. Subsequent reaction with a variety of methylating agents rapidly generates the desired [11C-carbonyl]-methylcarbamates in high radiochem. yields. The usefulness of the method is illustrated by the efficient radiosynthesis of a kappa opioid receptor imaging radiotracer, [11C]-GR103545, useful in positron emission tomog.
- 34Taddei, C.; Gee, A. D. Recent progress in [11C]carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) chemistry. J. Labelled Compd. Radiopharm. 2018, 61, 237– 251, DOI: 10.1002/jlcr.3596[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1Wnu7s%253D&md5=85da8695e14ceabc45fa7eeaf5895c47Recent progress in [11C]carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) chemistryTaddei, Carlotta; Gee, Antony D.Journal of Labelled Compounds and Radiopharmaceuticals (2018), 61 (3), 237-251CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)[11C]Carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) are 2 attractive precursors for labeling the carbonyl position (CO) in a vast range of functionalised mols. (eg, ureas, amides, and carboxylic acids). The development of radiosynthetic methods to produce functionalised 11C-labeled compds. is required to enhance the radiotracers available for positron emission tomog., mol., and medical imaging applications. Following a brief summary of secondary 11C-precursor prodn. and uses, the review focuses on recent progress with direct 11C-carboxylation routes with [11C]CO2 and 11C-carbonylation with [11C]CO. Novel approaches to generate [11C]CO using CO-releasing mols. (CO-RMs), such as silacarboxylic acids and disilanes, applied to radiochem. are described and compared with std. [11C]CO prodn. methods. These innovative [11C]CO synthesis strategies represent efficient and reliable [11C]CO prodn. processes, enabling the widespread use of [11C]CO chem. within the wider radiochem. community.
- 35Eriksson, J.; Antoni, G.; Långström, B.; Itsenko, O. The development of 11C- carbonylation chemistry: A systematic view. Nuclear Medicine and Biology 2020, DOI: 10.1016/j.nucmedbio.2020.02.005
- 36Taddei, C.; Pike, V. W. [11C]Carbon monoxide: Advances in production and application to PET radiotracer development over the past 15 years. EJNMMI Radiopharmacy and Chemistry. 2019, 4, 25, DOI: 10.1186/s41181-019-0073-4[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MjisVCltQ%253D%253D&md5=fab5f957b3e21fb707b66231df502116(11)C]Carbon monoxide: advances in production and application to PET radiotracer development over the past 15 yearsTaddei Carlotta; Pike Victor WEJNMMI radiopharmacy and chemistry (2019), 4 (1), 25 ISSN:.[(11)C]Carbon monoxide is an appealing synthon for introducing carbon-11 at a carbonyl position (C=O) in a wide variety of chemotypes (e.g., amides, ketones, acids, esters, and ureas). The prevalence of the carbonyl group in drug molecules and the present-day broad versatility of carbonylation reactions have led to an upsurge in the production of this synthon and in its application to PET radiotracer development. This review focuses on the major advances of the past 15 years.
- 37Hooker, J. M.; Schönberger, M.; Schieferstein, H.; Fowler, J. S. A simple, rapid method for the preparation of [11C]formaldehyde. Angew. Chem., Int. Ed. 2008, 47, 5989– 5992, DOI: 10.1002/anie.200800991[Crossref], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpsleitL8%253D&md5=d03c476e24a5ac45417b508b5308b4cdA simple, rapid method for the preparation of [11C]formaldehydeHooker, Jacob M.; Schoenberger, Matthias; Shchieferstein, Hanno; Fowler, Joanna S.Angewandte Chemie, International Edition (2008), 47 (32), 5989-5992, S5989/1-S5989/10CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A PET project: A powerful reagent for the synthesis of positron-emitting imaging mols.-[11C]formaldehyde-is accessible from [11C]methyl iodide and trimethylamine N-oxide (TMAO) in high yields and under mild conditions. Easy access to [11C]formaldehyde expands the scope of the carbon-11 toolbox and will lead to new reaction methodol. and imaging compds.
- 38Luthra, S. K.; Pike, V. W.; Brady, F. Preparation of some NCA [1–11C]acid chlorides as labelling agents. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1990, 41, 471– 476, DOI: 10.1016/0883-2889(90)90007-4
- 39McCarron, J. A.; Turton, D. R.; Pike, V. W.; Poole, K. G. Remotely-controlled production of the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635, via 11C- carboxylation of an immobilized Grignard reagent. J. Labelled Compd. Radiopharm. 1996, 38, 941– 953, DOI: 10.1002/(SICI)1099-1344(199610)38:10<941::AID-JLCR906>3.0.CO;2-Y[Crossref], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xmt1Kqsbw%253D&md5=9c802c13824bf3933769550ad0146b68Remotely-controlled production of the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635McCarron, Julie A.; Turton, David R.; Pike, Victor W.; Poole, Keith G.Journal of Labelled Compounds & Radiopharmaceuticals (1996), 38 (10), 941-953CODEN: JLCRD4; ISSN:0362-4803. (Wiley)N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide labeled in the carbonyl position with 11C (I), an effective radioligand for the study of 5-HT1A receptors in human brain by positron emission tomog., was prepd. Thus, cyclohexylmagnesium chloride coated on the inner surface of a narrow polypropylene tube was carboxylated by cyclotron-produced 11CO2 followed by passage of SOCl2 to convert the trapped radioactive adduct and to release the labeling agent into a vial contg. 1-(2-methoxyphenyl)-4-[2-(2-pyridylamino)ethyl]piperazine. The procedure was readily adapted for operation in a shielded hot-cell with remote control for radiation safety. The remotely-controlled radiosynthesis takes 45 min and gives high radioactivities (2.96-5.92 GBq) of I in >99% radiochem. purity and high specific radioactivity (av. 192 GBq/μmol).
- 40Marazano, C.; Maziere, M.; Berger, G.; Comar, D. Synthesis of methyl iodide-11C and formaldehyde-11C. Int. J. Appl. Radiat. Isot. 1977, 28, 49– 52, DOI: 10.1016/0020-708X(77)90159-4[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXktFyntrg%253D&md5=70689828769597881ebba801d609cd29Synthesis of methyl iodide-11C and formaldehyde-11CMarazano, Christian; Maziere, Mariannick; Berger, Gerard; Comar, DominiqueInternational Journal of Applied Radiation and Isotopes (1977), 28 (1-2), 49-52CODEN: IJARAY; ISSN:0020-708X.A fast 2-stage method of prepg. H211CO and 11CH3I is described. 11CO2 was reduced to 11CH3OH by LiAlH4 in THF, this product leading to H211CO by oxidn. on Ag catalyst or to 11CH3I by reaction with HI. It is easy to methylate certain chem. groups by use of these 2 mols. and the method was used to label substance of biol. interest for research in vivo. The sp. activity at the moment of use is 20-30 mCi/μmol, which indicates a high isotopic dilution.
- 41Joshi, R. K.; Goud, N. S.; Nagaraj, C.; Kumar, D.; R, G.; Rao, N. P.; Dhawan, A.; Bhattacharya, A.; Mangalore, S.; Bharath, R. D.; Kumar, P. Radiosynthesis Challenges of 11C and 18F-Labeled Radiotracers in the FX2C/N Tracerlab and Their Validation through PET-MR Imaging. Appl. Radiat. Isot. 2021, 168, 109486, DOI: 10.1016/j.apradiso.2020.109486[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1Gqsb3K&md5=2ccc954fd055aa8488e5fff5514e4eb9Radiosynthesis challenges of 11C and 18F-labeled radiotracers in the FX2C/N tracerlab and their validation through PET-MR imagingJoshi, Raman Kumar; Goud, Nerella Sridhar; Nagaraj, Chandana; Kumar, Dinesh; R, Gopinath; Rao, Naren P.; Dhawan, Anmol; Bhattacharya, Ahana; Mangalore, Sandhya; Bharath, Rose Dawn; Kumar, PardeepApplied Radiation and Isotopes (2021), 168 (), 109486CODEN: ARISEF; ISSN:0969-8043. (Elsevier Ltd.)Glucose is the renowned source of the energy for the cancer growth, that's the reason for [18F]FDG success and make it widely used radiotracer. Though [18F]FDG has its own inherent limitations therefore many tracers have been developed to target specific receptors, and other metabolic routes. We have used FX2C and FX2N Tracerlab modules for the synthesis of the [11C]methionine, [18F]choline and [18F]fluorodopa via nucleophilic pathway in FX2C/N module. [11C]methionine was standardized in FX2C module using two different precursors, and purified using C18 cartridge based technique. [18F]methylcholine was synthesized using dimethylaminoethanol precursor and purified using cartridge-based method. [18F]fluorodopa was synthesized using nucleophilic precursor and purified using in-built preparative HPLC on FX2N module. All radioactive intermediates and chem. impurities were evaluated by anal. HPLC. The radiochem. purity of D and L-[11C]methionine were 4.6 ± 3.2% and 95.4 ± 3.6% while other chem. impurities were less than prescribed limits with yield of 20 ± 5%. [18F]fluoromethylcholine was prepd. with high radiochem. purity of 97.3 ± 2.6% with yield of 8 ± 3%. [18F]fluorodopa was synthesized with high radiochem. purity of 95.8 ± 1.4% with 15 ± 3% yield. The adaptation of [18F]fluorodopa synthesis to FX2N module via designing synthesis sequence and purified through online HPLC has provided high radiochem. purity. PET-MR imaging was done using these tracers which have validated the synthesis and their availability for future clin. applications.
- 42Schoeps, K.-O.; Långström, B.; Stone-Elander, S.; Halldin, C. Synthesis of [1–11C]d- glucose and [1–11C]d-mannose from on-line produced [11C]nitromethane. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1991, 42, 877– 883, DOI: 10.1016/0883-2889(91)90228-S[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK38%252FktV2msQ%253D%253D&md5=9f6284b2c531c31466cd8e07e4d22f75Synthesis of [1-11C]D-glucose and [1-11C]D-mannose from on-line produced [11C]nitromethaneSchoeps K O; Langstrom B; Stone-Elander S; Halldin CInternational journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes (1991), 42 (9), 877-83 ISSN:0883-2889.A method for the preparation of [1-11C]D-glucose (III) and [1-11C] D-mannose (IV) from [11C] nitromethane is described. [11C]Nitromethane was produced using the on-line method from [11C]methyl iodide. The condensation of no-carrier-added or carrier-added [11C]nitromethane with D-arabinose to form the intermediate epimeric [1-11C]D-nitro alcohols (I and II) was investigated under various conditions. Compounds I and II were converted to III and IV by the classical Nef reaction with IV as the major product [(IV)/(III) = 3/1-4/1]. The isolated radiochemical yield of III and IV was 25-30% (based on [11C]nitromethane and decay-corrected) and 14-17% (EOB) with a total synthesis time of 50 min, including HPLC-purification. Compounds III and IV were isolated using semi-preparative HPLC and the radiochemical purity was greater than 97%. In a typical run, 1.5-2.0 mCi of III and 6-8 mCi of IV could be isolated (starting from 70-90 mCi [11C]nitromethane).
- 43Kadirvel, M.; Cardoso, D.; Freeman, S.; Brown, G. Radiosynthesis and reactivity of N- [11C]methyl carbamoylimidazole. J. Radioanal. Nucl. Chem. 2018, 317, 977– 984, DOI: 10.1007/s10967-018-5948-4[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFOmsbbI&md5=90fd0864da52030388eada1898fcab0eRadiosynthesis and reactivity of N-[11C]methyl carbamoylimidazoleKadirvel, Manikandan; Cardoso, Deborah; Freeman, Sally; Brown, GavinJournal of Radioanalytical and Nuclear Chemistry (2018), 317 (2), 977-984CODEN: JRNCDM; ISSN:0236-5731. (Springer)A new chem. route for synthesis of N-Me carbamoylimidazole from Me iodide was developed as an safe alternative to Me isocyanate for carbamoylation reaction and applied this to the synthesis of N-[11C]methyl carbamoylimidazole as a new [11C]synthon to radiolabel biomols. for PET imaging research. N-[11C]methyl carbamoylimidazole was prepd. from [11C]methyl iodide in 70-74% radiochem. yield (decay cor.) and was used in-situ for further reaction without purifn. The reactivity of N-[11C]methyl carbamoylimidazole was demonstrated in a series of [11C]carbamoylation reactions.
- 44Jewett, D. M. A simple synthesis of [11C]methyl triflate. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1992, 43, 1383– 1385, DOI: 10.1016/0883-2889(92)90012-4[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s%252FosVGjsw%253D%253D&md5=145672eefe5e62481fa86b1a5d0abfc4A simple synthesis of [11C]methyl triflateJewett D MInternational journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes (1992), 43 (11), 1383-5 ISSN:0883-2889.[11C]Methyl triflate ([11C]methyl trifluoromethanesulfonate) was formed in high yield when [11C]methyl iodide in a nitrogen carrier was passed at 200 degrees C through a column containing graphitized carbon impregnated with 50% by weight of silver triflate.
- 45Haywood, T.; Kealey, S.; Sánchez-Cabezas, S.; Hall, J. J.; Allott, L.; Smith, G.; Plisson, C.; Miller, P. W. Carbon-11 radiolabelling of organosulfur compounds: 11C synthesis of the progesterone receptor agonist tanaproget. Chem. - Eur. J. 2015, 21, 9034– 9038, DOI: 10.1002/chem.201501089[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotlCqtLY%253D&md5=5c84cfaff7732ef34652770bea10e29bCarbon-11 Radiolabelling of Organosulfur Compounds: 11C Synthesis of the Progesterone Receptor Agonist TanaprogetHaywood, Tom; Kealey, Steven; Sanchez-Cabezas, Santiago; Hall, James J.; Allott, Louis; Smith, Graham; Plisson, Christophe; Miller, Philip W.Chemistry - A European Journal (2015), 21 (25), 9034-9038CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Herein, a new 11C radiolabelling strategy for the fast and efficient synthesis of thioureas and related derivs. using the novel synthon, 11CS2, is reported. This approach has enabled the facile labeling of a potent progesterone receptor (PR) agonist, [11C]Tanaproget, by the intramol. reaction of the acyclic aminohydroxyl precursor with 11CS2, which has potential applications as a positron emission tomog. radioligand for cancer imaging.
- 46Shao, X.; Rodnick, M. E.; Brooks, A. F.; Scott, P. J. H. Synthesis and Applications of [11C]Hydrogen Cyanide. In Radiochemical Syntheses; Scott, P. J. H., Ed.; John Wiley & Sons, Inc: Hoboken, NJ, 2015; pp 233– 240.
- 47Haskali, M. B.; Pike, V. W. [11C]fluoroform, a breakthrough for versatile labeling of PET radiotracer trifluoromethyl groups in high molar activity. Chem. - Eur. J. 2017, 23, 8156– 8160, DOI: 10.1002/chem.201701701[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvVCqtL4%253D&md5=1097b58d7010f9d83232a988621af5bd[11C]Fluoroform, a Breakthrough for Versatile Labeling of PET Radiotracer Trifluoromethyl Groups in High Molar ActivityHaskali, Mohammad B.; Pike, Victor W.Chemistry - A European Journal (2017), 23 (34), 8156-8160CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Positron-emission tomog. (PET) is an immensely important imaging modality in biomedical research and drug development but must use selective radiotracers to achieve biochem. specificity. Such radiotracers are usually labeled with carbon-11 (t1/2=20 min) or fluorine-18 (t1/2=110 min), but these are only available from cyclotrons in a few simple chem. forms. [18F]Fluoroform has emerged for labeling tracers in trifluoromethyl groups but is severely limited in utility by low radioactivity per mass (low molar activity). Here, the synthesis of [11C]fluoroform is described, based on CoF3-mediated fluorination of cyclotron-produced [11C]methane. This process is efficient and repetitively reliable. [11C]Fluoroform shows versatility for labeling small mols. in very high molar activity (>200 GBq μmol-1), far exceeding that possible by using [18F]fluoroform. Therefore, [11C]fluoroform represents a major breakthrough for labeling prospective PET tracers in trifluoromethyl groups at high molar activity.
- 48Roeda, D.; Dolle, F. [11C]Phosgene: A versatile reagent for radioactive carbonyl insertion into medicinal radiotracers for positron emission tomography. Curr. Top. Med. Chem. 2010, 10, 1680– 1700, DOI: 10.2174/156802610793176710[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1ahtrrO&md5=197a317eeac308494cb0bc65b11d74fb[11C]Phosgene, a versatile reagent for radioactive carbonyl insertion into medicinal radiotracers for positron emission tomographyRoeda, Dirk; Dolle, FredericCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (16), 1680-1700CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. [11C]phosgene was playing a relatively modest but continuous and manifest role all along the history of radiochem. for Positron Emission Tomog. It acts as a radiolabeling agent through carbonyl insertion, usually between heteroatoms, and benefits from a high chem. reactivity allowing for short reaction times. This review gave an overview of this radiochem. from its beginning until the present day. After drawing up the inventory of the various ways of its prodn., the reactions in which it was employed and the labeled products that were synthesized with it are cataloged. This comprises the reactions of [11C]phosgene with primary, secondary and tertiary amines to labeled isocyanates and carbamoyl chlorides, which serve as intermediates for sym. and unsym. [11C]ureas and [11C]carbamates, reactions with alcs. leading to labeled carbamates and carbonates via [11C]chloroformates, cyclization reactions to heterocycles and the radiochem. of the secondary radiolabeling agents [11C]urea and diethyl- or di-Me [11C]carbonate. Apart from this already vast field of chem. possibilities there should be room for extension of the use of [11C]phosgene to other chem., notably that of C-11C bond formation.
- 49Landais, P.; Crouzel, C. A new synthesis of carbon-11 labelled phosgene. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1987, 38, 297– 300, DOI: 10.1016/0883-2889(87)90042-6
- 50Szlosek-Pinaud, M.; Allard, M.; Fouquet, E.; James, D. State of art in 11C labelled radiotracers synthesis. Curr. Med. Chem. 2008, 15, 235– 277, DOI: 10.2174/092986708783497292[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsVyisrc%253D&md5=3373ad7cc94dfe53fcaf6114b0ddaa63State of art in 11C labelled radiotracers synthesisAllard, M.; Fouquet, E.; James, D.; Szlosek-Pinaud, M.Current Medicinal Chemistry (2008), 15 (3), 235-277CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Positron Emission Tomog. has become a powerful scientific and clin. tool probing biochem. processes in the human body. Their clin. applications have proven to be vital in the evaluation and diagnosis of diseases. This is due, in large part, to advances in instrumentation and synthetic chem. Carbon-11 is a valuable radionuclide in PET as it virtually permits the synthesis of radiolabeled versions of any compd. of interest. The syntheses with carbon-11 present several features: limited no. of labeled precursors, sub-micromolar amts. of the starting materials, and a need for the introduction of the radioisotope as late as possible in the synthesis. All of these reasons have restricted complex radiosyntheses. The short half-life of carbon-11 (20.4 min) requires the rapid prepn. and purifn. of carbon-11 labeled mols. Those have to be carried out immediately before use from cyclotron produced precursors ([11C]CO2, [11C]CO, [11C]CH4) or reagents rapidly prepd. from them ([11C]CH3I, [11C]COCI2, [11C]HCN). As a consequence carbon-11 has been underused compared to fluorine-18. However, because of the increasing mol. complexity and diversity of biol. active compds., there is a need for new methodologies giving access in short time and high yield to radioactive 11C-probes. The aim of this review is to emphasize the methodologies used in this field and to give a comprehensive overview of the numerous advances, which occurred over the past decade. In addn., for each labeling technique or reaction reported, a special attention has been brought to classify the applications in function of the targeted medical domain.
- 51Wuest, F.; Berndt, M.; Kniess, T. Carbon-11 Labeling Chemistry Based upon [11C]Methyl Iodide. In PET Chemistry; Schubiger, P. A., Lehmann, L., Friebe, M., Eds.; Springer: Berlin Heidelberg, 2007; Vol. 64, pp 183– 213.
- 52Pekošak, A.; Filp, U.; Poot, A. J.; Windhorst, A. D. From carbon-11-labeled amino acids to peptides in positron emission tomography: The synthesis and clinical application. Molecular Imaging and Biology. 2018, 20, 510– 532, DOI: 10.1007/s11307-018-1163-5[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlantLY%253D&md5=60ce7e563ca3435241808637189e242fFrom Carbon-11-Labeled Amino Acids to Peptides in Positron Emission Tomography: the Synthesis and Clinical ApplicationPekosak, Aleksandra; Filp, Ulrike; Poot, Alex J.; Windhorst, Albert D.Molecular Imaging and Biology (2018), 20 (4), 510-532CODEN: MIBOCZ; ISSN:1860-2002. (Springer)A review. Radiolabeled amino acids, their derivs. and peptides have a broad scope of application and can be used as receptor ligands, as well as enzyme substrates for many different diseases as radiopharmaceutical tracers. Over the past few decades, the application of mol. imaging techniques such as positron emission tomog. (PET) has gained considerable importance and significance in diagnosis in today's advanced health care. Next to that, the availability of cyclotrons and state-of-the-art radiochem. facilities has progressed the prodn. of imaging agents enabling the prepn. of many versatile PET radiotracers. Due to many favorable characteristics of radiolabeled amino acids and peptides, they can be used for tumor staging and monitoring the progress of therapy success, while arom. amino acids can be employed as PET tracer to study neurol. disorders. This review provides a comprehensive overview of radiosynthetic and enzymic approaches towards carbon-11 amino acids, their analogs and peptides, with focus on stereoselective reactions, and reflects upon their clin. application.
- 53Antoni, G.; Kihlberg, T.; Långström, B. 11C: Labeling Chemistry and Labeled Compounds. In Handbook of Nuclear Chemistry; Vértes, A., Nagy, S., Klencsár, Z., Lovas, R. G., Rösch, F., Eds.; Springer US: Boston, MA, 2011; pp 1977– 2019.
- 54Correa, A.; Martín, R. Metal-catalyzed carboxylation of organometallic reagents with carbon dioxide. Angew. Chem., Int. Ed. 2009, 48, 6201– 6204, DOI: 10.1002/anie.200900667[Crossref], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpvFyhu7s%253D&md5=ca4ad574034905a13582de19db7e7c74Metal-Catalyzed Carboxylation of Organometallic Reagents with Carbon DioxideCorrea, Arkaitz; Martin, RubenAngewandte Chemie, International Edition (2009), 48 (34), 6201-6204CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Review on the recent advances in metal catalyzed carboxylation of organometallic reagents with carbon dioxide.
- 55Duffy, I. R.; Vasdev, N.; Dahl, K. Copper(I)-mediated 11C-carboxylation of (hetero)arylstannanes. ACS Omega. 2020, 5, 8242– 8250, DOI: 10.1021/acsomega.0c00524[ACS Full Text
], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvF2gsb8%253D&md5=4603e151e132f20e060af207c3deaff9Copper(I)-Mediated 11C-Carboxylation of (Hetero)arylstannanesDuffy, Ian R.; Vasdev, Neil; Dahl, KennethACS Omega (2020), 5 (14), 8242-8250CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)A novel copper-mediated carboxylation strategy of aryl- and heteroaryl-stannanes was described. The method served as a mild (i.e., 1 atm) carboxylation method using stable carbon dioxide and was transferable as a radiosynthetic approach for carbon-11-labeled arom. and heteroarom. carboxylic acids using sub-stoichiometric quantities of [11C]CO2. The methodol. was applied to the radiosynthesis of the retinoid X receptor agonist, [11C]bexarotene, with a decay-cor. radiochem. yield of 32 ± 5% and molar activity of 38 ± 23 GBq/μmol (n = 3). - 56Doi, H. Pd-mediated rapid cross-couplings using [(11)C]methyl iodide: Groundbreaking labeling methods in (11)C radiochemistry. J. Labelled Compd. Radiopharm. 2015, 58, 73– 85, DOI: 10.1002/jlcr.3253[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkvVaitb8%253D&md5=9055f285dc63e8ae5dccfd9607bdd5f9Pd-mediated rapid cross-couplings using [11C]methyl iodide: ground breaking labeling methods in 11C radiochemistryDoi, HisashiJournal of Labelled Compounds and Radiopharmaceuticals (2015), 58 (3), 73-85CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)A review. This paper presents a short summary of the background and the development of Pd-mediated rapid cross-couplings of [11C]methyl iodide, with a focus not only on organostannanes, but also on organoboranes, organozincs, and terminal acetylene compds. All these reactions have proven to be dependable 11C-labeling methodologies that use chem. reliable carbon-carbon bond formation reactions.
- 57Foresti, R.; Motterlini, R. Interaction of carbon monoxide with transition metals: Evolutionary insights into drug target discovery. Curr. Drug Targets 2010, 11, 1595– 1604, DOI: 10.2174/1389450111009011595[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKrtrbF&md5=7829af4aa2fd64d1405e1fe37985019cInteraction of carbon monoxide with transition metals: evolutionary insights into drug target discoveryForesti, Roberta; Motterlini, RobertoCurrent Drug Targets (2010), 11 (12), 1595-1604CODEN: CDTUAU; ISSN:1389-4501. (Bentham Science Publishers Ltd.)A review. The perception that carbon monoxide (CO) is poisonous and life-threatening for mammalian organisms stems from its intrinsic propensity to bind iron in Hb, a reaction that ultimately leads to impaired oxygen delivery to tissues. From evolutionary and chem. perspectives, however, CO is one of the most essential mols. in the formation of biol. components and its interaction with transition metals is at the origin of primordial cell signaling. Not surprisingly, mammals have gradually evolved systems to finely control the synthesis and the sensing of this gaseous mol. Cells are indeed continuously exposed to small quantities of CO produced endogenously during the degrdn. of heme by constitutive and inducible heme oxygenase enzymes. We have gradually learnt that heme oxygenase-derived carbon monoxide (CO) serves as a ubiquitous signaling mediator which could be exploited for therapeutic purposes. The development of transition metal carbonyls as prototypic carbon monoxide-releasing mols. (CO-RMs) represents a novel stratagem for a safer delivery of CO-based pharmaceuticals in the treatment of various pathol. disorders. This review looks back at evolution to analyze and argue that a dynamic interaction of CO with specific intracellular metal centers is the common denominator for the diversified beneficial effects mediated by this gaseous mol.
- 58Pretze, M.; Große-Gehling, P.; Mamat, C. Cross-coupling reactions as valuable tool for the preparation of PET radiotracers. Molecules 2011, 16, 1129– 1165, DOI: 10.3390/molecules16021129[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvFansrw%253D&md5=4f6701c98a520885e716fbd7836ce4eeCross-coupling reactions as valuable tool for the preparation of PET radiotracersPretze, Marc; Grosse-Gehling, Philipp; Mamat, ConstantinMolecules (2011), 16 (), 1129-1165CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. The increasing application of positron emission tomog. (PET) in nuclear medicine stimulated the extensive development of a multitude of new radiotracers and novel radiolabeling procedures with the most prominent short-lived positron emitters carbon-11 and fluorine-18. Radiolabeling with these radionuclides represents a remarkable challenge. Special attention paid to synthesis time and specific labeling techniques due to the short phys. half life of the resp. radionuclides 11C (t1/2 = 20.4 min) and 18F (t1/2 = 109.8 min). In the past, numerous transition metal-catalyzed reactions were employed in org. chem., even though only a handful of these coupling reactions were adopted in radiochem. practice. Thus, the implementation of modern synthesis methods like cross-coupling reactions offers the possibility to develop a wide variety of novel radiotracers. The introduction of catalysts based on transition metal complexes bears a high potential for rapid, efficient, highly selective and functional group-tolerating incorporation of carbon-11 and fluorine-18 into target mols. This review dealt with design, application and improvement of transition metal-mediated carbon-carbon as well as carbon-heteroatom cross-coupling reactions as a labeling feature with the focus on the prepn. of radiolabeled compds. for mol. imaging.
- 59Dahl, K.; Schou, M.; Amini, N.; Halldin, C. Palladium-mediated [11C]carbonylation at atmospheric pressure: A general method using xantphos as supporting ligand: Pd-mediated [11C]carbonylation at atmospheric pressure. Eur. J. Org. Chem. 2013, 2013, 1228– 1231, DOI: 10.1002/ejoc.201201708[Crossref], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1eqsLk%253D&md5=8753261cbe35114ce6ec315e823b42eePalladium-Mediated [11C]Carbonylation at Atmospheric Pressure: A General Method Using Xantphos as Supporting LigandDahl, Kenneth; Schou, Mangus; Amini, Nahid; Halldin, ChristerEuropean Journal of Organic Chemistry (2013), 2013 (7), 1228-1231CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)The palladium-catalyzed [11C]carbonylation of aryl halides and triflates was achieved at atm. pressure by employing xantphos as the supporting ligand. Aryl halides were converted into their corresponding [11C]amides in good to excellent yields. The conditions were also successfully employed in the radiolabeling of an [11C]ester, a [11C]carboxylic acid, an [11C]aldehyde, and a [11C]ketone.
- 60Xu, Y.; Kim, S. W.; Kim, D.; Alexoff, D.; Schueller, M. J.; Fowler, J. S. A mild, rapid synthesis of freebase [11C]nicotine from [11C]methyl triflate. Appl. Radiat. Isot. 2016, 118, 62– 66, DOI: 10.1016/j.apradiso.2016.08.020[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyit73J&md5=b7c1520f5d2c5fb4b5b27624b321f382A mild, rapid synthesis of freebase [11C]nicotine from [11C]methyl triflateXu, Youwen; Kim, Sung Won; Kim, Dohyun; Alexoff, David; Schueller, Michael J.; Fowler, Joanna S.Applied Radiation and Isotopes (2016), 118 (), 62-66CODEN: ARISEF; ISSN:0969-8043. (Elsevier Ltd.)A rapid, mild radiosynthesis of free base [11C]nicotine was developed by the methylation of free base nornicotine with [11C]methyl triflate in acetone (5 min, 45 °C). A basic (pH 10.5-11.0) HPLC system reproducibly yielded free base [11C]nicotine as a well-defined single peak. The free base [11C]nicotine was concd. by solid phase extn. and formulated in 50 μL ethanol (370 MBq/50 μL) without evaporative loss suitable for a cigarette spiking study. A radiochem. yield of 60.4±4.7% (n = 3), radiochem. purity ≥99.9% and specific activity of 648 GBq/μmol at EOB for 5 min beams were achieved.
- 61Saji, H.; Magata, Y.; Yamada, Y.; Tajima, K.; Yonekura, Y.; Konishi, J.; Ohmomo, Y.; Yokoyama, A. Synthesis of (S)-N-(methyl-11C)nicotine and its regional distribution in the mouse brain: A potential tracer for visualization of brain nicotinic receptors by positron emission tomography. Chem. Pharm. Bull. 1992, 40, 734– 736, DOI: 10.1248/cpb.40.734[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XisFWiurw%253D&md5=64e5aeaf8e65541a6685cc225d53a6f5Synthesis of (S)-N-[methyl[11C]nicotine and its regional distribution in the mouse brain: a potential tracer for visualization of brain nicotinic receptors by positron emission tomographySaji, Hideo; Magata, Yasuhiro; Yamada, Yoshihisa; Tajima, Ken; Yonekura, Yoshiharu; Konishi, Junji; Ohmomo, Yoshiro; Yokoyama, AkiraChemical & Pharmaceutical Bulletin (1992), 40 (3), 734-6CODEN: CPBTAL; ISSN:0009-2363.A nicotine agonist, 11C-labeled (S)-nicotine, was synthesized by N-methylation of (S)-nornicotine with 11CH3I Me iodide in DMS-DMSO to study nicotinic receptors in the human brain by positron emission tomog. The radiochem. yield of this N-methylation reaction was >90% within 5 min. After purifn. by HPLC the radiochem. purity of the product was >99% and the specific radioactivity was 7.4-11.1 GBq/μmol. The regional distribution of (S)-[11C]nicotine in the mouse brain after i.v. injection was compared with that of (R)-[11C]nicotine. After injection of (S)-[11C]nicotine, the regional uptake of radioactivity was in the following order: cortex > thalamus ≈ hippocampus > striatum > hypothalamus > cerebellum. Moreover, (S)-[11C]nicotine was displaced from the brain by unlabeled (S)-nicotine, but unlabeled (R)-nicotine caused no change in uptake. In contrast, (R)-[11C]nicotine showed a lower brain uptake and lesser regional differences in radioactivity.
- 62Ettrup, A.; Mikkelsen, J. D.; Lehel, S.; Madsen, J.; Nielsen, E. O.; Palner, M.; Timmermann, D. B.; Peters, D.; Knudsen, G. M. 11C-NS14492 as a novel PET Radioligand for imaging cerebral 7 nicotinic acetylcholine receptors: In vivo evaluation and drug occupancy measurements. J. Nucl. Med. 2011, 52, 1449– 1456, DOI: 10.2967/jnumed.111.088815[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1yisrrE&md5=31dc0d035440f28a9c6f9187c066832011C-NS14492 as a novel PET radioligand for imaging cerebral α7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurementsEttrup, Anders; Mikkelsen, Jens D.; Lehel, Szabolcs; Madsen, Jacob; Nielsen, Elsebet O.; Palner, Mikael; Timmermann, Daniel B.; Peters, Dan; Knudsen, Gitte M.Journal of Nuclear Medicine (2011), 52 (9), 1449-1456CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Small-mol. α7 nicotinic acetylcholine receptor (α7nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α7nAChR PET tracer would be important for in vivo quantification of α7nAChR binding in humans and to measure α7nAChR occupancy of α7nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of 11C-NS14492 as a selective α7nAChR PET radioligand. Methods: The high-affinity α7nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using 11C-Me triflate. Female Danish Landrace pigs were studied at baseline and after i.v. administration of blocking doses of either the α7nAChR partial agonist SSR180711 or the unlabeled NS14492. 11C-NS14492 was given as an i.v. bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compd. fraction was detd. with radio-high-performance liq. chromatog. PET data were quantified with a graphical anal. with arterial input; 11C-NS14492 regional distribution vols. were calcd., and α7nAChR occupancy was detd. using an occupancy plot. Results: 11C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α7nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution vols. of 11C-NS14492 in all examd. regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α7nAChR in vivo. Conclusion: We report here that 11C-NS14492 is the first, to our knowledge, PET radioligand for α7nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compd. is considered a promising PET tracer for in vivo measurements of α7nAChR binding in the human brain.
- 63Cai, L.; Xu, R.; Guo, X.; Pike, V. W. Rapid room-temperature 11C-methylation of arylamines with [11C]methyl iodide promoted by solid inorganic-bases in DMF. Eur. J. Org. Chem. 2012, 2012, 1303– 1310, DOI: 10.1002/ejoc.201101499[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xkt1CjtA%253D%253D&md5=ee3feec44d6a1a7f0201707d0800081eRapid Room-Temperature 11C-Methylation of Arylamines with [11C]Methyl Iodide Promoted by Solid Inorganic-Bases in DMFCai, Lisheng; Xu, Rong; Guo, Xuelei; Pike, Victor W.European Journal of Organic Chemistry (2012), 2012 (7), 1303-1310CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)[11C]Methyl iodide is the most widely used reagent for labeling radiotracers with carbon-11 (t1/2 = 20.4 min) for mol. imaging with positron emission tomog. However, some substrates for labeling, esp. primary arylamines and pyrroles, are sluggishly reactive towards [11C]methyl iodide. We found that insol. inorg. bases, esp. Li3N or Li2O, effectively promote rapid reactions (≤ 10 min) of such substrates with no-carrier-added [11C]methyl iodide in N,N-dimethylformamide (DMF) at room temp. to give 11C-methylated products, e.g. I, in useful radiochem. yields. In particular, we discovered that some primary arylamines in Li3N/DMF were converted into their corresponding formanilides, and that these were readily N-methylated with [11C]methyl iodide, which preceded easy basic hydrolysis to the desired [11C]N-Me secondary arylamines. The use of a solid base permitted selective reaction at an arylamino group and, in some cases, avoided undesirable side reactions, such as ester group hydrolysis. An ultrasound device proved useful to provide remote and const. agitation of the radioactive heterogeneous reaction mixts. but imparted no ultrasound-specific chem. effect.
- 64Slobbe, P.; Windhorst, A. D.; Adamzek, K.; Bolijn, M.; Schuit, R. C.; Heideman, D. A. M.; van Dongen, G. A. M. S.; Poot, A. J. Development of [11C]vemurafenib employing a carbon-11 carbonylative stille coupling and preliminary evaluation in mice bearing melanoma tumor xenografts. Oncotarget 2017, 8, 38337– 38350, DOI: 10.18632/oncotarget.16321[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cvoslKjtg%253D%253D&md5=21c2f985920c4b0536188d2f1c53fe81Development of [11C]vemurafenib employing a carbon-11 carbonylative Stille coupling and preliminary evaluation in mice bearing melanoma tumor xenograftsSlobbe Paul; Windhorst Albert D; Adamzek Kevin; Bolijn Marije; Schuit Robert C; van Dongen Guus A M S; Poot Alex J; Slobbe Paul; van Dongen Guus A M S; Heideman Danielle A MOncotarget (2017), 8 (24), 38337-38350 ISSN:.Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAFV600E mutation. The aim of this study was to develop vemurafenib as PET tracer to determine its potential for identification of tumors sensitive to vemurafenib treatment. Therefore, vemurafenib was labeled with carbon-11 and analyzed for its tumor targeting potential in melanoma xenografts Colo829 (BRAFV600E) and MeWo (BRAFwt) using autoradiography on tissue sections, in vitro tumor cell uptake studies and biodistribution studies in xenografted athymic nu/nu mice. [11C]vemurafenib was synthesized in 21 ± 4% yield (decay corrected, calculated from [11C]CO) in > 99% radiochemical purity and a specific activity of 55 ± 18 GBq/μmol. Similar binding of [11C]vemurafenib was shown during autoradiography and cellular uptake studies in both cell lines. Plasma metabolite analysis demonstrated > 95% intact [11C]vemurafenib in vivo at 45 minutes after injection, indicating excellent stability. Biodistribution studies confirmed the in vitro results, showing similar tumor-to-background ratios in both xenografts models. These preliminary results suggest that identification of BRAFV600E mutations in vivo using PET with [11C]vemurafenib will be challenging.
- 65Garcia, R.; Xavier, C.; Paulo, A.; Santos, I.; Kniess, T.; Bergmann, R.; Wüst, F. Synthesis and biological evaluation of S-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT 1A receptors by positron emission tomography (PET). J. Labelled Compd. Radiopharm. 2005, 48, 301– 315, DOI: 10.1002/jlcr.924[Crossref], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjslWrtb0%253D&md5=3b649a7ebe504dac27f0166aae75d44fSynthesis and biological evaluation of S-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT1A receptors by positron emission tomography (PET)Garcia, Raquel; Xavier, Catarina; Paulo, Antonio; Santos, Isabel; Kniess, Torsten; Bergmann, R.; Wuest, FrankJournal of Labelled Compounds & Radiopharmaceuticals (2005), 48 (4), 301-315CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)The novel 2-mercaptoimidazole derivs., 1-[4-((2-methoxyphenyl)-1-piperazinyl)-butyl]-2-mercaptoimidazole (3) and methyl[4-((2-methoxyphenyl)-1-piperazinyl))butyl] (2-mercapto-1-methylimidazol-5-yl)methanamide (8), were efficiently labeled with 11C through methylation of the thioketone function with [11C]methyl iodide. The resulting radioligands 1-[4-((2-methoxyphenyl)-1-piperazinyl))butyl]-2-thio[11C]-methylimidazole ([11C]9) and methyl[4-((2-methoxyphenyl)-1-piperazinyl))butyl] (2-thio[11C]methyl-1-methylimidazol-5-yl)-methanamide ([11C]10) were synthesized in radiochem. yields of 20-30% (decay-cor., related to [11C]CO2) at a specific radioactivity of 0.2-0.4 Ci/μmol within 40-45 min including HPLC-purifn. The radiochem. purity exceeded 99%. The ref. compds. 9 and 10 were tested in a competitive receptor binding assay to det. their affinity toward the 5-HT1A receptor. Both compds. exhibit excellent sub-nanomolar affinities (IC50 = 0.576 ± 0.008 nM (9); IC50 = 0.86 ± 0.02 nM (10)) for the 5-HT1A receptor while displaying a high selectivity towards the 5-HT2A subtype of receptors (IC50 > 480 nM). By contrast, compd. 9 also shows substantial binding for the alpha1-adrenergic receptor (IC50 = 3.00 ± 0.02 nM) when compared with compd. 10 (IC50 = 54.5 ± 0.6 nM). Preliminary biodistribution studies in rats showed an initial. Brain uptake of 1.14 ± 0.11 and 0.37 ± 0.04% ID/g after 5 min, which decreased to 0.18 ± 0.04 and 0.16 ± 0.01% ID/g after 60 min for compds. [11C]9 and [11C]10, resp. For both compds., the cerebellum and rest of the brain uptake are very similar at the different time points. Unlike [11C]9, the radioligand [11C]10 has significant uptake and retention in the adrenal glands. Due to their washout from the brain compds. [11C]9 and [11C]10 seem not to be good candidates as radioligands for imaging 5-HT1A receptors by PET.
- 66Roger, G.; Lagnel, B.; Besret, L.; Bramoullé, Y.; Coulon, C.; Ottaviani, M.; Kassiou, M.; Bottlaender, M.; Valette, H.; Dollé, F. Synthesis, radiosynthesis and in vivo evaluation of 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-[11C]one, as a potent NR1A/2B subtype selective NMDA PET radiotracer. Bioorg. Med. Chem. 2003, 11, 5401– 5408, DOI: 10.1016/j.bmc.2003.09.036[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpt1egu7k%253D&md5=9be98f98e659b6cd479eb14ef1407a5dSynthesis, radiosynthesis and In vivo evaluation of 5-[3-(4-Benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-[11C]one, as a potent NR1A/2B subtype selective NMDA PET radiotracerRoger, Gaelle; Lagnel, Beatrice; Besret, Laurent; Bramoulle, Yann; Coulon, Christine; Ottaviani, Michelle; Kassiou, Michael; Bottlaender, Michel; Valette, Heric; Dolle, FredericBioorganic & Medicinal Chemistry (2003), 11 (24), 5401-5408CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Recently, a new series of potent and highly subtype-selective 1-(heteroarylalkynyl)-4-benzylpiperidine antagonists of the NMDA receptors has been described by Pfizer Labs. In this series, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-one (I) was identified as a selective antagonist for the NR1A/2B subtype, displaying IC50 values for inhibition of the NMDA responses of 5.3 nM for this subtype (compared to NR1A/2A: 35 μM and NR1A/2C>100 μM) and was active in rat at a relatively low dosage (10 mg/kg po). Deriv. I has been synthesized in four chem. steps in good overall yield and labeled with carbon-11 T12: 20.4 min at its benzoimidazolone ring using [11C]phosgene. The pharmacol. profile of [11C]-I was evaluated in vivo in rats with biodistribution studies and brain radioactivity monitored with intracerebral radiosensitive β-microprobes. The brain uptake of [11C]-I was extremely low (0.07% I.D./mL on av. at 30 min) and rather uniform across the different brain structures. This in vivo brain regional distribution of [11C]-I did not match with autoradiog. or binding data obtained with other NR2B subtype-selective NMDA ligands. Competition studies with ifenprodil (20 mg/kg, i.p., 30 min before the radiotracer injection) failed to demonstrate specific binding of the radiotracer in the brain. In view of these results, and esp. considering the low brain penetration of the radiotracer, [11C]-I does not have the required properties for imaging NMDA receptors using positron emission tomog.
- 67Bramoullé, Y.; Puech, F.; Saba, W.; Valette, H.; Bottlaender, M.; George, P.; Dollé, F. Radiosynthesis of (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl] oxazolidin-2-[11C]one ([11C]SL25.1188), a novel radioligand for imaging monoamine oxidase-B with PET. J. Labelled Compd. Radiopharm. 2008, 51, 153– 158, DOI: 10.1002/jlcr.1492[Crossref], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlvVKgtrc%253D&md5=fbb2ba59a37fd1350c7b4efefac9c4f3Radiosynthesis of (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl]oxazolidin-2-[11C]one ([11C]SL25.1188), a novel radioligand for imaging monoamine oxidase-B with PETBramoulle, Yann; Puech, Frederic; Saba, Wadad; Valette, Heric; Bottlaender, Michel; George, Pascal; Dolle, FredericJournal of Labelled Compounds and Radiopharmaceuticals (2008), 51 (3), 153-158CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)Within a novel series of 2-oxazolidinones developed in the past by Sanofi-Synthelabo, I (SL25.1188), a compd. that inhibits selectively and competitively MAO-B in human and rat brain (Ki values of 2.9 and 8.5 nM for MAO-B, resp., and ED50 (rat): 0.6 mg/kg p.o.), was considered an appropriate candidate for imaging this enzyme with positron emission tomog. I was labeled with carbon-11 (T1/2: 20.38 min) in one chem. step using the following process: (i) reaction of [11C]phosgene with the corresponding ring-opened precursor (1.2-2.5 mg) at 100 °C for 2 min in dichloromethane (0.5 mL) followed by (ii) concn. to dryness of the reaction mixt. and finally (iii) semi-preparative HPLC purifn. on a Waters Symmetry C18. A total of 300-500 MBq of [11C]-I (>95% chem. and radiochem. pure) could be obtained within 30-32 min (Sep-pak-based formulation included) with specific radioactivities ranging from 50 to 70 GBq/μmol (3.5-7% decay-cor. radiochem. yield, based on starting [11C]CH4).
- 68Hicks, J. W.; Parkes, J.; Tong, J.; Houle, S.; Vasdev, N.; Wilson, A. A. Radiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors. Nucl. Med. Biol. 2014, 41, 688– 694, DOI: 10.1016/j.nucmedbio.2014.05.001[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFentb3M&md5=dcedea3b995995c96c88e7fa130378faRadiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitorsHicks, Justin W.; Parkes, Jun; Tong, Junchao; Houle, Sylvain; Vasdev, Neil; Wilson, Alan A.Nuclear Medicine and Biology (2014), 41 (8), 688-694CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are the two primary enzymes that regulate the tone of endocannabinoid signaling. Although new PET radiotracers have been discovered for imaging FAAH in vivo, no such radiotracer exists for imaging MAGL. Here we report the radiosynthesis of five candidate MAGL radiotracers and their ex vivo evaluations in mice and rats.Candidate carbamate and urea MAGL inhibitors were radiolabeled at the carbonyl position by [11C]CO2 fixation. Radiotracers were administered (tail-vein injection) to rodents and brain uptake of radioactivity measured at early and late time points ex vivo. Specificity of uptake was explored by pretreatment with unlabeled inhibitors (2 mg/kg, i.p.) 30 min prior to radiotracer administration.All five candidate MAGL radiotracers were prepd. in high specific activity (> 65 GBq/μmol) and radiochem. purity (> 98%). Moderate brain uptake (0.2-0.8 SUV) was obsd. for each candidate while pretreatment did not reduce uptake for four of the five tested. For two candidates ([11C]12 and [11C]14), high retention of radioactivity was obsd. in the blood (ca. 10 and 4 SUV at 40 min) which was blocked by pretreatment with unlabeled inhibitors. The most promising candidate, [11C]18, demonstrated moderate brain uptake (ca. 0.8 SUV) which showed circa 50% blockade by pretreatment with unlabeled 18.One putative and four reported potent and selective MAGL inhibitors have been radiolabeled via [11C]CO2 fixation as radiotracers for this enzyme. Despite the promising in vitro pharmacol. profile, none of the five candidate radiotracers exhibited in vivo behavior suitable for PET neuroimaging.
- 69Wei, W.; Ni, D.; Ehlerding, E. B.; Luo, Q.-Y.; Cai, W. PET imaging of receptor tyrosine kinases in cancer. Mol. Cancer Ther. 2018, 17, 1625– 1636, DOI: 10.1158/1535-7163.MCT-18-0087[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVWrtrfL&md5=946d240d1ac024860ba3dc54f3b5e70ePET Imaging of Receptor Tyrosine Kinases in CancerWei, Weijun; Ni, Dalong; Ehlerding, Emily B.; Luo, Quan-Yong; Cai, WeiboMolecular Cancer Therapeutics (2018), 17 (8), 1625-1636CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Overexpression and/or mutations of the receptor tyrosine kinase (RTK) subfamilies, such as epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), are closely assocd. with tumor cell growth, differentiation, proliferation, apoptosis, and cellular invasiveness. Monoclonal antibodies (mAb) and tyrosine kinase inhibitors (TKI) specifically inhibiting these RTKs have shown remarkable success in improving patient survival in many cancer types. However, poor response and even drug resistance inevitably occur. In this setting, the ability to detect and visualize RTKs with noninvasive diagnostic tools will greatly refine clin. treatment strategies for cancer patients, facilitate precise response prediction, and improve drug development. Positron emission tomog. (PET) agents using targeted radioactively labeled antibodies have been developed to visualize tumor RTKs and are changing clin. decisions for certain cancer types. In the present review, we primarily focus on PET imaging of RTKs using radiolabeled antibodies with an emphasis on the clin. applications of these immunoPET probes. Mol Cancer Ther; 17(8); 1625-36. ©2018 AACR.
- 70Li, L.; Liu, S.; Liu, L.; Ma, Z.; Feng, M.; Ye, C.; Zhou, W.; Wang, Y.; Liu, L.; Wang, F.; Yu, L.; Zhou, F.; Xiang, Y.; Huang, S.; Fu, Q.; Zhang, Q.; Gao, D.; Yu, Z. Impact of phosphorylated insulin-like growth factor-1 receptor on the outcome of breast cancer patients and the prognostic value of its alteration during neoadjuvant chemotherapy. Exp. Ther. Med. 2018, 16, 2949– 2959, DOI: 10.3892/etm.2018.6584[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czgs1CntA%253D%253D&md5=ad47d34dfb9cfc816f64511150917647Impact of phosphorylated insulin-like growth factor-1 receptor on the outcome of breast cancer patients and the prognostic value of its alteration during neoadjuvant chemotherapyLi Liang; Liu Shuchen; Liu Liyuan; Ma Zhongbing; Ye Chunmiao; Zhou Wenzhong; Wang Yongjiu; Liu Lu; Wang Fei; Yu Lixiang; Zhou Fei; Xiang Yujuan; Huang Shuya; Fu Qinye; Zhang Qiang; Gao Dezong; Yu Zhigang; Liu Shuchen; Ye Chunmiao; Zhou Wenzhong; Liu Lu; Feng ManExperimental and therapeutic medicine (2018), 16 (4), 2949-2959 ISSN:1792-0981.The expression of insulin-like growth factor-1 receptor (IGF-1R), which is involved in the genesis and progression of breast cancer, is thought to be associated with the overall survival (OS) of patients. However, the predictive and prognostic significance of the IGF-1R expression in breast cancer remains controversial. The present study aimed to identify the factors associated with the levels of phosphorylated (p)-IGF-1R in breast cancer, their impact on the outcomes of breast cancer patients, and the prognostic value of alterations of p-IGF-1R during neoadjuvant chemotherapy (NAC). The present study included 348 female breast cancer patients whose paraffin-embedded tumor tissue sections had been collected by biopsy and/or resection, among which the pre-NAC and post-NAC sections were available from 40 patients. Human epidermal growth factor receptor 2 (HER2) positivity and molecular subtype were significantly associated with the presence of p-IGF-1R in the tumor tissue (P<0.05). Patients with p-IGF-1R present in the tumor tissue had a shorter OS (P=0.003). The p-IGF-1R levels in the tumor after NAC differed significantly from those prior to NAC (P=0.005); however, this alteration in p-IGF-1R levels was not associated with a shorter OS. In parallel with HER2, p-IGF-1R appears to be a promising indicator for predicting clinical outcomes and may be an attractive target for improving the efficacy of antitumor therapy, particularly for patients with HER2-negative, estrogen receptor-positive and luminal B tumors.
- 71Tegnebratt, T.; Lu, L.; Eksborg, S.; Chireh, A.; Damberg, P.; Nikkhou-Aski, S.; Foukakis, T.; Rundqvist, H.; Holmin, S.; Kuiper, R. V.; Samen, E. Treatment response assessment with (R)-[11CPAQ PET in the MMTV-PyMT mouse model of breast cancer. EJNMMI Res. 2018, 8, 25, DOI: 10.1186/s13550-018-0380-x[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MnovVWiuw%253D%253D&md5=4bb2095c3613104b3793516da1e85c37Treatment response assessment with (R)-[(11)CPAQ PET in the MMTV-PyMT mouse model of breast cancerTegnebratt T; Lu L; Chireh A; Damberg P; Nikkhou-Aski S; Holmin S; Samen E; Tegnebratt T; Holmin S; Samen E; Lu L; Damberg P; Nikkhou-Aski S; Eksborg S; Foukakis T; Rundqvist H; Kuiper R VEJNMMI research (2018), 8 (1), 25 ISSN:2191-219X.BACKGROUND: The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[(11)C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models. METHODS: MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[(11)C]PAQ PET as standardized uptake value (SUV)mean, SUVmax relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[(11)C]PAQ radiotracer uptake and therapy response biomarkers. RESULTS: The (R)-[(11)C]PAQ SUVmax in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUVmax change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[(11)C]PAQ SUVmax change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups. CONCLUSIONS: The results of this study are promising. However, additional studies are necessary before (R)-[(11)C]PAQ can be approved as a predictive radiotracer for cancer therapy response.
- 72van Dongen, G. A. M. S.; Visser, G. W. M.; Lub-De Hooge, M. N.; de Vries, E. G.; Perk, L. R. Immuno-PET: A navigator in monoclonal antibody development and applications. Oncologist 2007, 12, 1379– 1389, DOI: 10.1634/theoncologist.12-12-1379[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhslSntLs%253D&md5=66ffadf35003a3866e6ce263a33dedd2Immuno-PET: a navigator in monoclonal antibody development and applicationsvan Dongen, Guus A. M. S.; Visser, Gerard W. M.; Lub-de Hooge, Marjolijn N.; de Vries, Elisabeth G.; Perk, Lars R.Oncologist (2007), 12 (12), 1379-1389CODEN: OCOLF6; ISSN:1083-7159. (AlphaMed Press)A review. Monoclonal antibodies (mAbs) have been approved for use as diagnostics and therapeutics in a broad range of medical indications, but esp. in oncol. In addn., hundreds of new mAbs, engineered mAb fragments, and nontraditional antibody-like scaffolds directed against either validated or novel tumor targets are under development. Immuno-positron emission tomog. (PET), the tracking and quantification of mAbs with PET in vivo, is an exciting novel option to improve diagnostic imaging and to guide mAb-based therapy. In this review, recent tech. advances leading to a jump ahead in mAb imaging are discussed. The availability of proper positron emitters, sophisticated radiochem., and advanced PET and PET-computed tomog. scanners is crucial in these developments. Immuno-PET might play an important future role in cancer staging, in the improvement and tailoring of therapy with existing mAbs, and in the efficient development of novel mAbs. An overview of the preclin. and first clin. immuno-PET studies is provided.
- 73Weber, B.; Winterdahl, M.; Memon, A.; Sorensen, B. S.; Keiding, S.; Sorensen, L.; Nexo, E.; Meldgaard, P. Erlotinib accumulation in brain metastases from non-small cell lung cancer: Visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J. Thorac. Oncol. 2011, 6, 1287– 1289, DOI: 10.1097/JTO.0b013e318219ab87[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MjmvV2rsA%253D%253D&md5=a00d4acc3aec6b71157da49fdf4732f0Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptorWeber Britta; Winterdahl Michael; Memon Ashfaque; Sorensen Boe S; Keiding Susanne; Sorensen Leif; Nexo Ebba; Meldgaard PeterJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2011), 6 (7), 1287-9 ISSN:.INTRODUCTION: Drugs directed toward the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva®) and gefitinib (Iressa®), are used for the treatment of patients with advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. However, whether erlotinib actually enters into brain metastases has not been adequately elucidated. In this study, we investigated the accumulation of [11C]-erlotinib by positron emission tomography (PET) combined with computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: A 32-year-old patient with NSCLC and multiple brain metastases was treated with first-line erlotinib. EGFR mutations were determined by analyzing a fine-needle lung tumor biopsy taken before the treatment. A PET/CT of the brain with [11C]-erlotinib was performed during treatment, and a MRI of the head and a CT of the chest were performed pre- and posttreatment. RESULTS: The primary lung tumor displayed an erlotinib-sensitizing exon 19 deletion in the EGFR gene, and [11C]-erlotinib PET/CT showed accumulation in the brain metastases. Posttreatment MRI and CT demonstrated regression of both brain metastases and primary lung tumor. CONCLUSION: Our data demonstrated that erlotinib accumulated in brain metastases in a NSCLC patient who responded to the treatment.
- 74Saleem, A.; Searle, G. E.; Kenny, L. M.; Huiban, M.; Kozlowski, K.; Waldman, A. D.; Woodley, L.; Palmieri, C.; Lowdell, C.; Kaneko, T.; Murphy, P. S.; Lau, M. R.; Aboagye, E. O.; Coombes, R. C. Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer. EJNMMI Res. 2015, 5, 30, DOI: 10.1186/s13550-015-0103-5[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfktlOgtQ%253D%253D&md5=244029e3a9f8a69486ffba1fb4e56bfdLapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancerSaleem Azeem; Searle Graham E; Huiban Mickael; Kenny Laura M; Kozlowski Kasia; Aboagye Eric O; Coombes Raoul C; Waldman Adam D; Woodley Laura; Palmieri Carlo; Lowdell Charles; Kaneko Tomomi; Murphy Philip S; Lau Mike REJNMMI research (2015), 5 (), 30 ISSN:2191-219X.BACKGROUND: Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access. METHODS: Patients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([(11)C]lapatinib)-PET. Less than 20 μg of [(11)C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted. RESULTS: Six patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [(11)C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [(11)C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [(11)C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib. CONCLUSIONS: Increased lapatinib uptake was observed in brain metastases but not in normal brain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01290354.
- 75Varrone, A.; Varnäs, K.; Jucaite, A.; Cselényi, Z.; Johnström, P.; Schou, M.; Vazquez-Romero, A.; Moein, M. M.; Halldin, C.; Brown, A. P.; Vishwanathan, K.; Farde, L. A PET study in healthy subjects of brain exposure of 11C-labelled osimertinib - A drug intended for treatment of brain metastases in non-small cell lung cancer. J. Cereb. Blood Flow Metab. 2020, 40, 799– 807, DOI: 10.1177/0271678X19843776[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvF2qsbg%253D&md5=a466648d161c31693a18f1b314c2653bA PET study in healthy subjects of brain exposure of 11C-labelled osimertinib - A drug intended for treatment of brain metastases in non-small cell lung cancerVarrone, Andrea; Varnaes, Katarina; Jucaite, Aurelija; Cselenyi, Zsolt; Johnstroem, Peter; Schou, Magnus; Vazquez-Romero, Ana; Moein, Mohammad M.; Halldin, Christer; Brown, Andrew P.; Vishwanathan, Karthick; Farde, LarsJournal of Cerebral Blood Flow & Metabolism (2020), 40 (4), 799-807CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)Osimertinib is a tyrosine kinase inhibitor (TKI) of mutated epidermal growth factor receptor (EGFRm) with obsd. efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to det. brain distribution and exposure of 11C-labeled osimertinib administered i.v. in subjects with an intact blood-brain barrier. Eight male healthy subjects (age 52 ± 8 years) underwent one PET measurement with 11C-osimertinib. The pharmacokinetic parameters Cmax(brain) (standardized uptake value), Tmax(brain) and AUC0-90 minbrain/blood ratio were calcd. The outcome measure for 11C-osimertinib brain exposure was the total distribution vol. (VT). 11C-osimertinib distributed rapidly to the brain, with higher uptake in gray than in white matter. Mean Cmax, Tmax and AUC0-90 minbrain/blood ratio were 1.5 (range 1-1.8), 13 min (range 5-30 min), and 3.8 (range 3.3-4.1). Whole brain and white matter VT were 14 mLxcm-3 (range 11-18) and 7 mLxcm-3 (range 5-12). This study in healthy volunteers shows that 11C-osimertinib penetrates the intact blood-brain barrier. The approach used further illustrates the role of mol. imaging in facilitating the development of novel drugs for the treatment of malignancies affecting the brain.
- 76Zheng, Q.-H.; Stone, K. L.; Mock, B. H.; Miller, K. D.; Fei, X.; Liu, X.; Wang, J.-Q.; Glick-Wilson, B. E.; Sledge, G. W.; Hutchins, G. D. [11C]choline as a potential PET marker for imaging of breast cancer athymic mice. Nucl. Med. Biol. 2002, 29, 803– 807, DOI: 10.1016/S0969-8051(02)00339-6[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XovFKjt7g%253D&md5=dc6660a52cdaf28546afd5e20512d6bf[11C]choline as a potential PET marker for imaging of breast cancer athymic miceZheng, Qi-Huang; Stone, K. Lee; Mock, Bruce H.; Miller, Kathy D.; Fei, Xiangshu; Liu, Xuan; Wang, Ji-Quan; Glick-Wilson, Barbara E.; Sledge, George W.; Hutchins, Gary D.Nuclear Medicine and Biology (2002), 29 (8), 803-807CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)[11C]Choline has been evaluated as a potential positron emission tomog. (PET) marker for imaging of breast cancer. The biodistribution of [11C]choline was detd. at 45 min post iv injection in MCF-7's transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptake of [11C]choline in these tumors was high, 2.0% dose/g in MCF-7's transfected with IL-1alpha implanted mice and 1.8% dose/g in MDA-MB-435 implanted mice; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.7 (T/M, MCF-7's), 2.1 (T/M, MDA-MB-435) and 6.9 (T/B, MCF-7's), 12.5 (T/B, MDA-MB-435), resp.; the tumor/muscle ratios are moderate, and the tumor/blood ratios are high. The micro-PET imaging of [11C]choline in both breast cancer athymic mice was acquired for 15 min from a MCF-7's transfected with IL-1alpha and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resoln. (<3 mm full-width at half-max.) small FOV (field-of-view) PET imaging system, Indy-PET II scanner, developed in our lab., which showed the uptake of [11C]choline in MCF-7's transfected with IL-1alpha tumor or MDA-MB-435 tumor implanted in a nude athymic mouse. These results suggest that [11C]choline may be a potential PET breast cancer imaging agent.
- 77Hara, T.; Kosaka, N.; Kishi, H. PET imaging of prostate cancer using carbon-11-choline. J. Nucl. Med. 1998, 39, 990– 995[PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXktV2itrg%253D&md5=8556569bbe8650e1792490774700e1e2PET imaging of prostate cancer using carbon-11-cholineHara, Toshihiko; Kosaka, Noboru; Kishi, HiroichiJournal of Nuclear Medicine (1998), 39 (6), 990-995CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Prostate cancer is difficult to visualize using current techniques. Recently, 31P magnetic resonance spectroscopy has revealed that the tumor, in general, is characterized by an increased uptake of choline into the cell to meet increased synthesis of phosphatidyl-choline, an important cell membrane phospholipid. We succeeded in using 11C-choline to visualize prostate cancer and its local metastasis in PET. PET was performed on 10 prostate cancer patients from the level of pelvis to the lower abdomen. After transmission scanning, 370 MBq 11C-choline were injected i.v. The emission scan was performed 5-15 min postinjection. Finally, PET images were displayed so that each pixel was painted by a specified color representing the degree of the standardized uptake value (SUV). The 11C-choline image was compared with the 18F-fluorodeoxyglucose (FDG) image obtained from the same patient. Imaging of prostate cancer and its local metastasis was difficult when 18F-FDG was used because, within the pelvis, the areas of high uptake were concealed by the overwhelmingly abundant radioactivity in urine (in ureters and bladder). By contrast, it was easy when 11C-choline was used because the urinary activity was negligible and tumor uptake was marked. The radioactivity concn. of 11C-choline in prostate cancer and metastatic sites was at an SUV of more than three in most cases. The SUV of 18F-FDG was considerably lower than that of 11C-choline. Prostate cancer and its local metastasis were visualized clearly in PET using 11C-choline.
- 78Hara, T.; Kosaka, N.; Shinoura, N.; Kondo, T. PET imaging of brain tumor with [methyl-11C]choline. J. Nucl. Med. 1997, 38, 842– 847[PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXksVWkurw%253D&md5=b027efcf9405dfeb049b5704f5bcc4bePET imaging of brain tumor with [methyl-11C]cholineHara, Toshihiko; Kosaka, Noboru; Shinoura, Nobusada; Kondo, TatsuyaJournal of Nuclear Medicine (1997), 38 (6), 842-847CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)This article describes a new method of [11C]choline synthesis for i.v. injection. We aimed at the utilization of this compd. for brain tumor imaging with PET. After [11C]carbon dioxide prodn. in a cyclotron and the subsequent [11C]methyl iodide synthesis, [methyl-11C]choline was synthesized by the reaction of [11C]methyl iodide with "neat" dimethylaminoethanol at 120°C for 5 min. Purifn. was achieved by evapn. of the reactants followed by passage of the aq. soln. of the product through a cation-exchange resin cartridge. The time required for overall chem. processing, excluding the cyclotron operation, was 15 min. Radiochem. yield was >98%. Radiochem. purity was >98%. Chem. purity was >90% (dimethylaminoethanol was the only possible impurity). Specific radioactivity of the product was >133 GBq/μmol. The whole body distribution was examd. in rabbits with PET. Clin. studies were performed in patients with brain tumor using PET after i.v. injection of 370 MBq of [11C]choline. In rabbits, [11C]choline was taken up from blood by various tissues very rapidly, and the radioactivity remaining in blood became almost negligible 5 min after i.v. injection. Taking advantage of this characteristic, we obtained stable tissue distribution images of human brain using PET. In patients with brain tumor, PET produced clearly delineated pos. images of the tumors. Carbon-11-choline can be used for obtaining clear images of brain tumor in PET.
- 79DeGrado, T. R.; Baldwin, S. W.; Wang, S.; Orr, M. D.; Liao, R. P.; Friedman, H. S.; Reiman, R.; Price, D. T.; Coleman, R. E. Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers. J. Nucl. Med. 2001, 42, 1805– 1814[PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XktlOktb8%253D&md5=5a95d32aa66f9089758b6890e3ca6bbcSynthesis and evaluation of 18F-labeled choline analogs as oncologic PET tracersDeGrado, Timothy R.; Baldwin, Steven W.; Wang, Shuyan; Orr, Matthew D.; Liao, Ray P.; Friedman, Henry S.; Reiman, Robert; Price, David T.; Coleman, R. EdwardJournal of Nuclear Medicine (2001), 42 (12), 1805-1814CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Elevated levels of choline (trimethyl-2-hydroxyethylammonium) and choline kinase (CK) activity in neoplasms have motivated the development of positron-labeled choline analogs for noninvasive detection of cancer using PET. The aim of this study was to further evaluate [18F]fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) as an oncol. probe in comparison with several other closely related mols. FCH, [18F]fluoromethyl-methylethyl-2-hydroxyethylammonium (FMEC), [18F]fluoroethyl-dimethyl-2-hydroxyethylammonium (FEC), and [18F]fluoropropyl-dimethyl-2-hydroxyethylammonium (FPC) were synthesized through [18F]fluoroalkylation reactions. In vitro phosphorylation rates of the 18F-labeled choline analogs and [methyl14C]choline (CH) were studied using yeast CK. Several choline radiotracers were also evaluated in cultured PC-3 human prostate cancer cells. Data on chem. stability, radiation dosimetry, and toxicity of FCH were obtained. PET studies with FCH were performed on a patient with prostate cancer and a patient with a brain tumor. FCH and FMEC revealed in vitro phosphorylation by CK that was similar to that of choline, whereas rates of phosphorylation of FEC and FPC were 30% (P < 0.01) and 60% (P < 0.01) lower, resp. Accumulations of FCH, CH, and FPC in cultured PC-3 cancer cells were comparable, whereas uptake of FEC was approx. one fifth that of FCH. Dosimetry ests. using FCH biodistribution data in mice indicated that the kidneys are radiation-dose-crit. organs for FCH. PET images of a patient with recurrent prostate cancer showed uptake of FCH in the prostatic bed and in metastases to lymph nodes. FCH PET showed uptake in malignancies in a patient with metastatic breast cancer. PET revealed FCH uptake in biopsy-proven recurrent brain tumor with little confounding uptake by normal brain tissues. The fluoromethyl choline analog FCH may serve as a probe of choline uptake and phosphorylation in cancer cells, whereas fluoroethyl (FEC) and fluoropropyl (FPC) analogs appear to have relatively poorer biol. compatibility. Preliminary PET studies on patients with prostate cancer and with breast cancer and brain tumor support further studies to evaluate the usefulness of FCH as an oncol. probe.
- 80Ohtani, T.; Kurihara, H.; Ishiuchi, S.; Saito, N.; Oriuchi, N.; Inoue, T.; Sasaki, T. Brain tumour imaging with carbon-11 choline: Comparison with FDG PET and gadolinium-enhanced MR imaging. Eur. J. Nucl. Med. 2001, 28, 1664– 1670, DOI: 10.1007/s002590100620[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvFGhsbY%253D&md5=209800ec166ef31348a286a8f16068a6Brain tumour imaging with carbon-11 choline: comparison with FDG PET and gadolinium-enhanced MR imagingOhtani, Toshiyuki; Kurihara, Hideyuki; Ishiuchi, Shogo; Saito, Nobuhito; Oriuchi, Noboru; Inoue, Tomio; Sasaki, TomioEuropean Journal of Nuclear Medicine (2001), 28 (11), 1664-1670CODEN: EJNMD9; ISSN:0340-6997. (Springer-Verlag)The purpose of this study was to assess the clin. potential of methyl-11C-choline (11C-choline) in the diagnosis of brain tumors. To this end, the results of 11C-choline positron emission tomog. (PET) in 22 patients suspected of having brain tumors were compared with the findings of contrast-enhanced magnetic resonance (MR) imaging and fluorine-18 fluorodeoxyglucose PET. A histopathol. diagnosis was made for each patient during open surgery. The standardized uptake values of brain tumors and the tumor-to-white matter count (T/W) ratios were detd. The degree of 11C-choline accumulation noted in PET images was compared with the gadolinium-enhanced areas of MR images. The mean T/W ratio of 11C-choline in high-grade gliomas was found to be higher than that in low-grade gliomas. This difference was statistically significant (mean±SD: 8.7±6.2, n=9 vs. 1.5±0.7, n=5, P<0.03) when data pertaining to the prominent uptake of 11C-choline in a patient with a pilocytic astrocytoma were excluded. 11C-choline PET failed to detect non-neoplastic lesions in two patients. Areas of 11C-choline accumulation in PET scans were larger than areas enhanced on MR images in five cases involving high-grade gliomas. 11C-choline PET differentiated between low-grade gliomas and high-grade gliomas, but did not differentiate between low-grade gliomas and non-neoplastic lesions. The combination of 11C-choline PET and MR imaging may provide investigators with an accurate means by which to identify high-grade gliomas.
- 81Giovacchini, G.; Fallanca, F.; Landoni, C.; Gianolli, L.; Picozzi, P.; Attuati, L.; Terreni, M.; Picchio, M.; Messa, C.; Fazio, F. C-11 choline versus F-18 fluorodeoxyglucose for imaging meningiomas: An initial experience. Clinical Nuclear Medicine. 2009, 34, 7– 10, DOI: 10.1097/RLU.0b013e31818f4369[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M%252FjvVKrtw%253D%253D&md5=42451271f4e399e339f6f7308963beb7C-11 choline versus F-18 fluorodeoxyglucose for imaging meningiomas: an initial experienceGiovacchini Giampiero; Fallanca Federico; Landoni Claudio; Gianolli Luigi; Picozzi Piero; Attuati Luca; Terreni Mariarosa; Picchio Maria; Messa Cristina; Fazio FerruccioClinical nuclear medicine (2009), 34 (1), 7-10 ISSN:.PURPOSE: Positron emission tomography/computed tomography (PET/CT) with C-11 choline has been used for staging, restaging, and follow-up of various tumors, whereas its role for imaging meningiomas has only been preliminarily explored. The aim of this study was to compare C-11 choline and F-18 fluorodeoxyglucose (F-18 FDG) uptake in meningiomas and relate these findings to the histopathological analysis. METHODS: Two sequential three-dimensional PET/CT scans with 370 MBq (10 mCi) of C-11 choline and 370 MBq (10 mCi) of F-18 FDG were performed 2 hours apart in 7 patients with histologically confirmed meningiomas. Five patients had WHO grade I and 2 had WHO grade II meningioma. For each scan, two-dimensional regions of interest were drawn on tumor boundaries and on the contralateral side on CT images and copied to the corresponding PET images. SUVmax and tumor-to-background ratio were calculated. RESULTS: Relative to the contralateral side, C-11 choline uptake was increased in all meningiomas, whereas F-18 FDG uptake was decreased in 6 patients and increased in 1 of the 2 patients with grade II meningiomas. In the whole group, SUVmax of C-11 choline and F-18 FDG were 3.6 +/- 1.3 and 5.7 +/- 1.3, respectively. The tumor-to-background ratio for C-11 choline was much higher than that for F-18 FDG (5.3 +/- 0.8 vs. 0.9 +/- 0.2, respectively) (P < 0.001). The uptake of C-11 choline was higher in patients with grade II than in grade I meningiomas. CONCLUSIONS: These preliminary results suggest that C-11 choline may better image meningiomas in comparison with F-18 FDG. Clinical applications of C-11 choline PET/CT for grading and follow-up of meningiomas need to be assessed in further studies.
- 82Giovannini, E.; Lazzeri, P.; Milano, A.; Gaeta, M.; Ciarmiello, A. Clinical applications of choline PET/CT in brain tumors. Curr. Pharm. Des. 2014, 21, 121– 127, DOI: 10.2174/1381612820666140915120742
- 83Giovacchini, G.; Picchio, M.; Garcia-Parra, R.; Mapelli, P.; Briganti, A.; Montorsi, F.; Gianolli, L.; Messa, C. [11C]choline positron emission tomography/computerized tomography for early detection of prostate cancer recurrence in patients with low increasing prostate specific antigen. J. Urol. 2013, 189, 105– 110, DOI: 10.1016/j.juro.2012.09.001[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s7ks1Wqsw%253D%253D&md5=0ba9d876db863f0955e1114e522b694711C]choline positron emission tomography/computerized tomography for early detection of prostate cancer recurrence in patients with low increasing prostate specific antigenGiovacchini Giampiero; Picchio Maria; Garcia-Parra Rita; Mapelli Paola; Briganti Alberto; Montorsi Francesco; Gianolli Luigi; Messa CristinaThe Journal of urology (2013), 189 (1), 105-10 ISSN:.PURPOSE: The effectiveness of salvage therapy in prostate cancer is greater for low prostate specific antigen values. Therefore, early detection of tumor recurrence is warranted. [(11)C]choline positron emission tomography/computerized tomography has the potential of early restaging of prostate cancer with low prostate specific antigen, but the selection of patients at high risk for positive [(11)C]choline positron emission tomography/computerized tomography is desirable to optimize salvage therapy. MATERIALS AND METHODS: This retrospective study included 75 patients with prostate cancer with an increasing prostate specific antigen less than 1.5 ng/ml after radical prostatectomy who never received antiandrogen deprivation therapy or salvage radiotherapy who underwent [(11)C]choline positron emission tomography/computerized tomography for the restaging of disease. Binary logistic regression was used to assess predictive factors of positive [(11)C]choline positron emission tomography/computerized tomography. Included variables were trigger prostate specific antigen, prostate specific antigen doubling time, age, pathological stage and Gleason score. RESULTS: Median prostate specific antigen was 0.61 ng/ml. [(11)C]choline positron emission tomography/computerized tomography was positive in 16 of 75 patients (21%). On univariate analysis prostate specific antigen doubling time less than 6 months was the only factor significantly associated with an increased risk of positive [(11)C]choline positron emission tomography/computerized tomography (OR 7.77, 95% CI 2.34-25.80, p = 0.001). In patients with prostate specific antigen doubling time less than 6 months, the positive detection rate of [(11)C]choline positron emission tomography/computerized tomography increased to 50%. CONCLUSIONS: In patients with prostate cancer with biochemical failure after radical prostatectomy and prostate specific antigen less than 1.5 ng/ml, prostate specific antigen doubling time less than 6 months predicts positive [(11)C]choline positron emission tomography/computerized tomography. In these patients [(11)C]choline positron emission tomography/computerized tomography may reduce by 50% the number in whom salvage therapy is initiated empirically without knowing the disease location.
- 84Lindenberg, L.; Choyke, P.; Dahut, W. Prostate cancer imaging with novel PET tracers. Curr. Urol Rep. 2016, 17, 18, DOI: 10.1007/s11934-016-0575-5[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jgslCksw%253D%253D&md5=2b6279d2c81159bf7f531436262f6016Prostate Cancer Imaging with Novel PET TracersLindenberg Liza; Choyke Peter; Dahut William; Lindenberg Liza; Choyke Peter; Dahut WilliamCurrent urology reports (2016), 17 (3), 18 ISSN:.Molecular imaging of prostate cancer is in a dynamic phase of development. Currently approved techniques are limited and researchers have been working on novel agents to improve accuracy in targeting and detecting prostate tumors. In addition, the complexity of various prostate cancer states also contributes to the challenges in evaluating suitable radiotracer candidates. We have highlighted nuclear medicine tracers that focus on mechanisms involved in bone metastasis, prostate cancer cell membrane synthesis, amino acid analogs, androgen analogs, and the prostate specific membrane antigen. Encouraging results with many of these innovative radiotracer compounds will not only advance diagnostic capabilities for prostate cancer but open opportunities for theranostic applications to treat this worldwide malignancy.
- 85Umbehr, M. H.; Muntener, M.; Hany, T.; Sulser, T.; Bachmann, L. M. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: A systematic review and meta-analysis. Eur. Urol. 2013, 64, 106– 117, DOI: 10.1016/j.eururo.2013.04.019[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3srptlWrug%253D%253D&md5=755f7d52261d4f2b62fd52651f7d4fe9The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysisUmbehr Martin H; Muntener Michael; Hany Thomas; Sulser Tullio; Bachmann Lucas MEuropean urology (2013), 64 (1), 106-17 ISSN:.CONTEXT: The role of positron emission tomography (PET) and PET/computed tomography (PET/CT) in prostate cancer (PCa) imaging is still debated, although guidelines for their use have emerged over the last few years. OBJECTIVE: To systematically review and conduct a meta-analysis of the available evidence of PET and PET/CT using 11C-choline and 18F-fluorocholine as tracers in imaging PCa patients in staging and restaging settings. EVIDENCE ACQUISITION: PubMed, Embase, and Web of Science (by citation of reference) were searched. Reference lists of review articles and included articles were checked to complement electronic searches. EVIDENCE SYNTHESIS: In staging patients with proven but untreated PCa, the results of the meta-analysis on a per-patient basis (10 studies, n = 637) showed pooled sensitivity, specificity, and diagnostic odds ratio (DOR) of 84% (95% confidence interval [CI], 68-93%), 79% (95% CI, 53-93%), and 20.4 (95% CI, 9.9-42.0), respectively. The positive and negative likelihood ratios were 4.02 (95% CI, 1.73-9.31) and 0.20 (95% CI, 0.11-0.37), respectively. On a per-lesion basis (11 studies, n = 5117), these values were 66% (95% CI, 56-75%), 92% (95% CI, 78-97%), and 22.7 (95% CI, 8.9-58.0), respectively, for pooled sensitivity, specificity, and DOR; and 8.29 (95% CI, 3.05-22.54) and 0.36 (95% CI, 0.29-0.46), respectively, for positive and negative likelihood ratios. In restaging patients with biochemical failure after local treatment with curative intent, the meta-analysis results on a per-patient basis (12 studies, n = 1055) showed pooled sensitivity, specificity, and DOR of 85% (95% CI, 79-89%), 88% (95% CI, 73-95%), and 41.4 (95% CI, 19.7-86.8), respectively; the positive and negative likelihood ratios were 7.06 (95% CI, 3.06-16.27) and 0.17 (95% CI, 0.13-0.22), respectively. CONCLUSIONS: PET and PET/CT imaging with 11C-choline and 18F-fluorocholine in restaging of patients with biochemical failure after local treatment for PCa might help guide further treatment decisions. In staging of patients with proven but untreated, high-risk PCa, there is limited but promising evidence warranting further studies. However, the current evidence shows crucial limitations in terms of its applicability in common clinical scenarios.
- 86Evangelista, L.; Zattoni, F.; Guttilla, A.; Saladini, G.; Zattoni, F.; Colletti, P. M.; Rubello, D. Choline PET or PET/CT and biochemical relapse of prostate cancer: A systematic review and meta-analysis. Clin Nucl. Med. 2013, 38, 305– 314, DOI: 10.1097/RLU.0b013e3182867f3c[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svlsVyqtQ%253D%253D&md5=f1af8c4db81e097a37afd0e5e53c8624Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysisEvangelista Laura; Zattoni Fabio; Guttilla Andrea; Saladini Giorgio; Zattoni Filiberto; Colletti Patrick M; Rubello DomenicoClinical nuclear medicine (2013), 38 (5), 305-14 ISSN:.AIM: The increase of prostate-specific antigen (PSA) after radical retropubic prostatectomy (RP) or external beam radiotherapy (EBRT) is the most sensitive tool for detecting prostate cancer (PCa) recurrence, although this measure cannot distinguish between local, regional, or distant recurrence. The aim of this meta-analysis was to evaluate the diagnostic performance of 18F-choline and 11C-choline PET or PET/CT in detection of locoregional or distant metastases in PCa. MATERIALS AND METHODS: Medline, Web of Knowledge, and Google Scholar search was carried out in order to select English-language articles dealing with diagnostic performance of both 18F-choline and 11C-choline PET for the detection of PCa recurrence after RP or EBRT. Articles were included only if absolute numbers of true-positive, true-negative, false-positive, and false-negative test results were available or derivable from the text and regarded local, lymph node, and distant metastases. Reviews, clinical reports, and editorial articles were excluded. All complete studies were re-analyzed thus performing a quantitative analysis. RESULTS: From the years 2000 to 2012, we found 53 complete articles that critically evaluated the role of choline PET in restaging patients with PCa recurrence. The meta-analysis was carried out and dealt with 19 selected studies (12 studies for all sites of disease, 3 for lymph node metastases, and 4 for local recurrence), with a total of 1555 patients. The meta-analysis provided a pooled sensitivity of 85.6% (95% CI: 82.9%-88.1%) and pooled specificity of 92.6% (95% CI: 90.1%-94.6%) for all sites of disease (prostatic fossa, lymph nodes, and bone), a pooled sensitivity of 75.4% (95% CI: 66.9%-82.6%) and pooled specificity of 82% (95% CI: 68.6%-91.4%) for prostatic fossa recurrence, and a pooled sensitivity of 100% (95% CI: 90.5%-100%) and pooled specificity of 81.8% (95% CI: 48.2%-97.7%) for lymph node metastases. The heterogeneity ranged between 0.00% and 88.6%. The diagnostic odds ratios were 62.123 (95% CI: 24.783-155.72), 5.869 (95% CI: 1.818-18.946), and 138.57 (95% CI: 11.27-1703.8), respectively, for all sites of disease, local recurrence, and lymph node disease. CONCLUSIONS: Choline PET and PET/CT represent high sensitivity and specificity techniques for the detection of locoregional and distant metastases in PCa patients with recurrence of disease. Moreover, a high diagnostic odds ratio was found for the identification of lymph node disease in patients with biochemical recurrence of PCa.
- 87Oyama, N.; Miller, T. R.; Dehdashti, F.; Siegel, B. A.; Fischer, K. C.; Michalski, J. M.; Kibel, A. S.; Andriole, G. L.; Picus, J.; Welch, M. J. 11C-acetate PET imaging of prostate cancer: Detection of recurrent disease at PSA relapse. J. Nucl. Med. 2003, 44, 549– 555[PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjtlKnsLY%253D&md5=74885bbe34c8f6839d0c38da14e989ec11C-Acetate PET imaging of prostate cancer: detection of recurrent disease at PSA relapseOyama, Nobuyuki; Miller, Tom R.; Dehdashti, Farrokh; Siegel, Barry A.; Fischer, Keith C.; Michalski, Jeff M.; Kibel, Adam S.; Andriole, Gerald L.; Picus, Joel; Welch, Michael J.Journal of Nuclear Medicine (2003), 44 (4), 549-555CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Patients with rising prostate-specific antigen (PSA) levels after definitive local therapy of prostate carcinoma present a diagnostic dilemma. A local recurrence would be amenable to addnl. local therapy with curative intent, whereas metastatic disease would require palliative androgen ablation therapy. In this study, we evaluated the effectiveness of PET with 11C-acetate (AC PET) for evaluation of patients with rising PSA after radical prostatectomy or radiation therapy. We also compared the reliability of AC PET in detecting recurrent prostate cancer with that of PET with 18F-FDG. Methods: Two groups of patients with PSA recurrence were enrolled in this study: group A, 30 patients after prostatectomy, and group B, 16 patients after radiation therapy. After administration of 1,110 MBq (30 mCi) of 11C-acetate, whole-body PET images were obtained. After allowing for 11C decay, 555 MBq (15 mCi) of 18F-FDG were administered and repeated whole-body imaging was performed. The PET findings were scored as pos. or neg. in each of the following regions: prostatic bed, pelvic nodes, paraaortic nodes, and other sites (bone or soft tissue). PET findings were correlated with those of CT, bone scintigraphy, and biopsy. Results: Twenty-seven of 46 AC PET studies (59%) had pos. findings, whereas only 8 18F-FDG PET studies had pos. findings (17%). Limiting the anal. to patients with findings confirmed by CT, bone scintigraphy, or biopsy or considered highly likely to represent tumor, 14 (30%) had disease identified by AC PET, whereas only 4 (9%) had disease identified by 18F-FDG PET. CT was performed on 22 patients and had pos. findings in 3 (14%). Thirteen of 22 patients (59%) with serum PSA > 3 ng/mL had pos. AC PET findings, whereas only 1 of 24 patients (4%) with serum PSA levels ≤ 3 ng/mL had pos. findings. Conclusion: AC PET demonstrates marked uptake in prostate cancer and has higher sensitivity than 18F-FDG PET. These preliminary data show that 11C-acetate is a promising tracer for detection of recurrent prostate cancer.
- 88Howard, B. V.; Howard, W. J. Lipids in normal and tumor cells in culture. Prog. Biochem. Pharmacol. 1975, 10, 135– 166[PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXksFKgsrY%253D&md5=6ef0957efd422856edc83a668acfac12Lipids in normal and tumor cells in cultureHoward, Barbara V.; Howard, William J.Progress in Biochemical Pharmacology (1975), 10 (Lipids Tumors), 135-66CODEN: PBPHAW; ISSN:0079-6085.A review with 153 refs., on the compn. and metab. of lipid classes (fatty acids, glycolipids, lipid esters, and phospholipids) in cells and membranes of cultured normal and neoplastic cells.
- 89Swinnen, J. V.; Van Veldhoven, P. P.; Timmermans, L.; De Schrijver, E.; Brusselmans, K.; Vanderhoydonc, F.; Van de Sande, T.; Heemers, H.; Heyns, W.; Verhoeven, G. Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem. Biophys. Res. Commun. 2003, 302, 898– 903, DOI: 10.1016/S0006-291X(03)00265-1[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhvFGqsLY%253D&md5=c0b853d5ab87ad8a10ec99d6b3e9d01fFatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomainsSwinnen, Johannes V.; Van Veldhoven, Paul P.; Timmermans, Leen; De Schrijver, Ellen; Brusselmans, Koen; Vanderhoydonc, Frank; Van de Sande, Tine; Heemers, Hannelore; Heyns, Walter; Verhoeven, GuidoBiochemical and Biophysical Research Communications (2003), 302 (4), 898-903CODEN: BBRCA9; ISSN:0006-291X. (Elsevier Science)Fatty acid synthase (FAS) is a key metabolic enzyme catalyzing the synthesis of long-chain satd. fatty acids. It plays a central role in the prodn. of surfactant in fetal lungs, in the supply of fatty components of milk, and in the conversion and storage of energy in liver and adipose tissue. Remarkably high levels of FAS expression are found in the majority of human epithelial cancers. As the role of FAS in cancer cells remains largely unknown, we have initiated studies to assess the fate of newly synthesized lipids in cancer cells and have estd. the contribution of FAS to the synthesis of specific lipid classes by treating the cells with small interfering RNAs targeting FAS. Here, we show that in cancer cells FAS plays a major role in the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. These are raft-aggregates implicated in key cellular processes including signal transduction, intracellular trafficking, cell polarization, and cell migration. These findings reveal a novel role for FAS, provide important new insights into the otherwise poorly understood mechanisms underlying the control of lipid compn. of membrane microdomains, and point to a link between FAS overexpression and dysregulation of membrane compn. and functioning in tumor cells.
- 90Buxton, D. B.; Nienaber, C. A.; Luxen, A.; Ratib, O.; Hansen, H.; Phelps, M. E.; Schelbert, H. R. Noninvasive quantitation of regional myocardial oxygen consumption in vivo with [1–11C]acetate and dynamic positron emission tomography. Circulation 1989, 79, 134– 142, DOI: 10.1161/01.CIR.79.1.134[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M%252FptVSrtQ%253D%253D&md5=67680ed1064f6603e8b45071638988f4Noninvasive quantitation of regional myocardial oxygen consumption in vivo with [1-11C]acetate and dynamic positron emission tomographyBuxton D B; Nienaber C A; Luxen A; Ratib O; Hansen H; Phelps M E; Schelbert H RCirculation (1989), 79 (1), 134-42 ISSN:0009-7322.The usefulness of [1-11C]acetate as a tracer of overall myocardial oxidative metabolism for use with positron emission tomography has been investigated in 12 closed-chest dogs. Myocardial 11C activity clearance kinetics after intravenous administration of [1-11C]acetate in dogs have been determined noninvasively by positron emission tomography. Biexponential fitting of regional myocardial 11C time-activity curves was performed to give clearance half-times and fractional distribution. The rate constant k1 for the early rapid phase of 11C activity clearance was found to correlate linearly with myocardial oxygen consumption (y = 0.0156x + 0.039; SEE = 0.023; r = 0.95). k1 was approximately 7% lower in septal sectors compared with the left ventricular free wall, suggesting that regional oxygen consumption in the septum was lower; a concomitant regional attenuation of blood flow in the septum relative to the left ventricular free wall was also observed. In dogs using carbohydrates as the predominant fuel, k1 oxygen consumption was somewhat more than in dogs using predominantly free fatty acids (0.021 +/- 0.002 compared with 0.018 +/- 0.002, p less than 0.01), indicating that increased carbohydrate consumption is associated with a small increase in k1 at constant oxygen consumption. It is concluded that measurement of myocardial [1-11C]acetate kinetics allows noninvasive determination of cardiac oxygen consumption by positron emission tomography and that the technique is relatively insensitive to myocardial fuel selection.
- 91Cerdan, S.; Künnecke, B.; Seelig, J. Cerebral metabolism of [1,2–13C2]acetate as detected by in vivo and in vitro 13C NMR. J. Biol. Chem. 1990, 265, 12916– 12926, DOI: 10.1016/S0021-9258(19)38247-X[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXkvFGhsbk%253D&md5=e59b2944465b9370d5d0d62099661e34Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro carbon-13 NMRCerdan, Sebastian; Kuennecke, Basil; Seelig, JoachimJournal of Biological Chemistry (1990), 265 (22), 12916-26CODEN: JBCHA3; ISSN:0021-9258.The metab. of [1,2-13C2]acetate in rat brain was studied by in vivo and in vitro 13C NMR spectroscopy, in particularly by taking advantage of the homonuclear 13C-13C spin coupling patterns. Well-nourished rats were infused with [1,2-13C2]acetate or [1-13C]acetate in the jugular vein, and the in situ kinetics of 13C labeling during the infusion period were followed by 13C NMR techniques. The in vivo 13C NMR spectra showed signals from (1) the C-1 carbon of [1,2-13C2]acetate or [1-13C]acetate, (2) 13CO3H-, and (3) the natural abundance 13C carbons of sufficiently mobile fatty acids. Methanol/HCl/perchloric acid exts. of the brains were prepd. and were further analyzed by high-resoln. 13C NMR. The homonuclear 13C-13C spin coupling patterns after infusion of [1,2-13C2]acetate showed very different isotopomer populations in glutamate, glutamine, and GABA. Analyzing the relative proportions of these isotopomers revealed (1) 2 different glutamate compartments in the rat brain characterized by the presence and absence, resp., of glutamine synthase activity, (2) 2 different tricarboxylic acid cycles, 1 preferentially metabolizing [(1,2-13C2]acetate, the other mainly using unlabeled acetyl-CoA, (3) a hitherto unknown cerebral pyruvate recycling system assocd. with the tricarboxylic acid cycle, metabolizing primarily unlabeled acetyl-CoA, and (4) a predominant product of GABA in the glutamate compartment lacking glutamine synthase.
- 92Yoshimoto, M.; Waki, A.; Yonekura, Y.; Sadato, N.; Murata, T.; Omata, N.; Takahashi, N.; Welch, M. J.; Fujibayashi, Y. Characterization of acetate metabolism in tumor cells in relation to cell proliferation: Acetate metabolism in tumor cells. Nucl. Med. Biol. 2001, 28, 117– 122, DOI: 10.1016/S0969-8051(00)00195-5[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXisVWnt70%253D&md5=22030db3d8daf072e827f0d64fe0fddfCharacterization of acetate metabolism in tumor cells in relation to cell proliferation: Acetate metabolism in tumor cellsYoshimoto, M.; Waki, A.; Yonekura, Y.; Sadato, N.; Murata, T.; Omata, N.; Takahashi, N.; Welch, M. J.; Fujibayashi, Y.Nuclear Medicine and Biology (2001), 28 (2), 117-122CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)To reveal the metabolic fate of acetate in neoplasms that may characterize the accumulation patterns of [1-11C]acetate in tumors depicted by positron emission tomog. Four tumor cell lines (LS174T, RPMI2650, A2780, and A375) and fibroblasts in growing and resting states were used. In uptake expts., cells were incubated with[1-14C]acetate for 40 min. [14C]CO2 was measured in the tight-air chamber, and the metabolites in cells were identified by thin layer chromatog. and paper chromatog. The glucose metabolic rate of each cell line was measured with [2,6-3H]2-deoxy-glucose (DG), and the growth activity of each cell line was estd. by measuring the incorporation of [3H]methyl thymidine into DNA. Compared with resting fibroblasts, all four tumor cell lines showed higher accumulation of 14C activity from [1-14C]acetate. These tumor-to-normal ratios of [1-14C]acetate were larger than those of DG. Tumor cells incorporated 14C activity into the lipid-sol. fraction, mostly of phosphatidylcholine and neutral lipids, more prominently than did fibroblasts. The lipid-sol. fraction of 14C accumulation in cells showed a pos. correlation with growth activity, whereas the water-sol. and CO2 fractions did not. These findings suggest that the high tumor-to-normal ratio of [1-14C]acetate is mainly due to the enhanced lipid synthesis, which reflects the high growth activity of neoplasms. This in vitro study suggests that [1-11C]acetate is appropriate for estg. the growth activity of tumor cells.
- 93Dimitrakopoulou-Strauss, A.; Strauss, L. G. PET imaging of prostate cancer with 11C-acetate. J. Nucl. Med. 2003, 44, 556– 558[PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7mt1eltA%253D%253D&md5=2ee69d02682668a76370b56204ced5f7PET imaging of prostate cancer with 11C-acetateDimitrakopoulou-Strauss Antonia; Strauss Ludwig GJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2003), 44 (4), 556-8 ISSN:0161-5505.There is no expanded citation for this reference.
- 94Delbeke, D.; Pinson, C. W. 11C-Acetate: A new tracer for the evaluation of hepatocellular carcinoma. J. Nucl. Med. 2003, 44, 222– 223[PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252FmtFSktQ%253D%253D&md5=7d00cbc64489fa0095429746b59fdb5711C-acetate: a new tracer for the evaluation of hepatocellular carcinomaDelbeke Dominique; Pinson C WrightJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2003), 44 (2), 222-3 ISSN:0161-5505.There is no expanded citation for this reference.
- 95Mena, E.; Turkbey, B.; Mani, H.; Adler, S.; Valera, V. A.; Bernardo, M.; Shah, V.; Pohida, T.; McKinney, Y.; Kwarteng, G.; Daar, D.; Lindenberg, M. L.; Eclarinal, P.; Wade, R.; Linehan, W. M.; Merino, M. J.; Pinto, P. A.; Choyke, P. L.; Kurdziel, K. A. 11C-Acetate PET/CT in localized prostate cancer: A study with MRI and histopathologic correlation. J. Nucl. Med. 2012, 53, 538– 545, DOI: 10.2967/jnumed.111.096032[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvFaqu7w%253D&md5=564ca4ce96766df577b106b7f2eb27cd11C-acetate PET/CT in localized prostate cancer: a study with MRI and histopathologic correlationMena, Esther; Turkbey, Baris; Mani, Haresh; Adler, Stephen; Valera, Vladimir A.; Bernardo, Marcelino; Shah, Vijay; Pohida, Thomas; McKinney, Yolanda; Kwarteng, Gideon; Daar, Dagane; Lindenberg, Maria L.; Eclarinal, Philip; Wade, Revia; Linehan, W. Marston; Merino, Maria J.; Pinto, Peter A.; Choyke, Peter L.; Kurdziel, Karen A.Journal of Nuclear Medicine (2012), 53 (4), 538-545CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)This work characterizes the uptake of 11C-acetate in prostate cancer (PCa), benign prostate hyperplasia, and normal prostate tissue in comparison with multiparametric MRI, whole-mount histopathol., and clin. markers to evaluate the potential utility of 11C-acetate for delineating intraprostatic tumors in a population of patients with localized PCa. Methods: Thirty-nine men with presumed localized PCa underwent dynamic-static abdominal-pelvic 11C-acetate PET/CT for 30 min and 3-T multiparametric MRI before prostatectomy. PET/CT images were registered to MR images using pelvic bones for initial rotation-translation, followed by manual adjustments to account for prostate motion and deformation from the MRI endorectal coil. Whole-mount pathol. specimens were sectioned using an MRI-based patient-specific mold resulting in improved registration between the MRI, PET, and pathol. 11C-acetate PET standardized uptake values were compared with multiparametric MRI and pathol. Results: 11C-acetate uptake was rapid but reversible, peaking at 3-5 min after injection and reaching a relative plateau at approx. 10 min. The av. max. standardized uptake value (10-12 min) of tumors was significantly higher than that of normal prostate tissue (4.4 ± 2.05 [range, 1.8-9.2] vs. 2.1 ± 0.94 [range, 0.7-3.4], resp.; P < 0.001); however, it was not significantly different from that of benign prostatic hyperplasia (4.8 ± 2.01 [range, 1.8-8.8]). A sector-based comparison with histopathol., including all tumors greater than 0.5 cm, revealed a sensitivity and specificity of 61.6% and 80.0%, resp., for 11C-acetate PET/CT and 82.3% and 95.1 %, resp., for MRI. The 11C-acetate accuracy was comparable to that of MRI when only tumors greater than 0.9 cm were considered. In a small cohort (n = 9), 11C-acetate uptake was independent of fatty acid synthase expression using immunohistochem. Conclusion: 11C-acetate PET/CT demonstrates higher uptake in tumor foci than in normal prostate tissue; however, 11C-acetate uptake in tumors is similar to that in benign prostate hyperplasia nodules. Although 11C-acetate PET/CT is not likely to have utility as an independent modality for evaluation of localized PCa, the high uptake in tumors may make it useful for monitoring focal therapy when tissue damage after therapy may limit anat. imaging methods.
- 96Mohsen, B.; Giorgio, T.; Rasoul, Z. S.; Werner, L.; Ali, G. R. M.; Reza, D. K. V.; Ramin, S. Application of C-11-acetate positron-emission tomography (PET) imaging in prostate cancer: Systematic review and meta-analysis of the literature. BJU Int. 2013, 112, 1062– 1072, DOI: 10.1111/bju.12279[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslCgur%252FJ&md5=3f08b8d11ccc55d3f5d7a3a14d8f067bApplication of 11C-acetate positron-emission tomography (PET) imaging in prostate cancer: systematic review and meta-analysis of the literatureMohsen, Beheshti; Giorgio, Treglia; Rasoul, Zakavi Seyed; Werner, Langsteger; Ali, Ghodsi Rad Mohammad; Reza, Dabbagh Kakhki Vahid; Ramin, SadeghiBJU International (2013), 112 (8), 1062-1072CODEN: BJINFO; ISSN:1464-410X. (Wiley-Blackwell)To review the literature on the application of 11C-acetate positron-emission tomog. (PET) imaging in prostate cancer. We systematically reviewed the available literature and presented the results in meta-anal. format. PubMed, SCOPUS, ISI web of knowledge, Science Direct, Springer, and Google Scholar were searched with 'Acetate AND PET AND Prostate' as keywords. All studies that evaluated accuracy of 11C-acetate imaging in primary or recurrent prostate cancer were included, if enough data could be extd. for calcn. of sensitivity and/or specificity. In all, 23 studies were included in the study. For evaluation of primary tumor, pooled sensitivity was 75.1 (69.8-79.8)% and specificity was 75.8 (72.4-78.9)%. For detection of recurrence, sensitivity was 64 (59-69)% and specificity was 93 (83-98)%. Sensitivity for recurrence detection was higher in post-surgical vs post-radiotherapy patients and in patients with PSA at relapse of >1 ng/mL. Studies using PET/computed tomog. vs PET also showed higher sensitivity for detection of recurrence. Imaging with 11C-acetate PET can be useful in patients with prostate cancer. This is esp. true for evaluation of patients at PSA relapse, although the sensitivity is overall low. For primary tumor evaluation (localisation of tumor in the prostate and differentiation of malignant from benign lesions), 11C-acetate is of limited value due to low sensitivity and specificity. Due to the poor quality of the included studies, the results should be interpreted with caution and further high-quality studies are needed.
- 97Sandblom, G.; Sörensen, J.; Lundin, N.; Häggman, M.; Malmström, P.-U. Positron emission tomography with c11-acetate for tumor detection and localization in patients with prostate-specific antigen relapse after radical prostatectomy. Urology. 2006, 67, 996– 1000, DOI: 10.1016/j.urology.2005.11.044[Crossref], [PubMed], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD283ntVeruw%253D%253D&md5=486a7ee52aef9c38cf1d3ec53795ef26Positron emission tomography with C11-acetate for tumor detection and localization in patients with prostate-specific antigen relapse after radical prostatectomySandblom Gabriel; Sorensen Jens; Lundin Niclas; Haggman Michael; Malmstrom Per-UnoUrology (2006), 67 (5), 996-1000 ISSN:.OBJECTIVES: To evaluate positron emission tomography with C11-acetate as a method for detecting and localizing prostate cancer recurrence. No technique for localizing and detecting prostate cancer recurrence after biochemical relapse available today is sensitive enough to localize recurrence at a stage at which salvage radiotherapy is still curative. METHODS: Twenty patients (age 56 to 77 years) who had undergone radical prostatectomy and had an increasing prostate-specific antigen level measured on two consecutive occasions were included. In addition to the investigations usually performed when prostate cancer recurrence is suspected, they underwent positron emission tomography with C11-acetate as the marker. RESULTS: Pathologic uptake of acetate was seen in 15 (75%) of the 20 patients. In 8 of these patients, a solitary lesion was found (seven in the prostatic fossa and one at the regional lymph nodes). Multiple lesions were found in the remaining 7. False-positive uptake was seen in 3 men (15%). Additional investigations in these men revealed pathologic findings other than prostate cancer. CONCLUSIONS: Positron emission tomography with C11-acetate as marker is a promising method for early detection and localization of prostate cancer recurrence. False-positive uptake does occur.
- 98Haseebuddin, M.; Dehdashti, F.; Siegel, B. A.; Liu, J.; Roth, E. B.; Nepple, K. G.; Siegel, C. L.; Fischer, K. C.; Kibel, A. S.; Andriole, G. L.; Miller, T. R. 11C-Acetate PET/CT before radical prostatectomy: Nodal staging and treatment failure prediction. J. Nucl. Med. 2013, 54, 699– 706, DOI: 10.2967/jnumed.112.111153[Crossref], [PubMed], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosFCns7k%253D&md5=d858c827db240024c6ca641b5987008c11C-acetate PET/CT before radical prostatectomy: nodal staging and treatment failure predictionHaseebuddin, Mohammed; Dehdashti, Farrokh; Siegel, Barry A.; Liu, Jingxia; Roth, Elizabeth B.; Nepple, Kenneth G.; Siegel, Cary L.; Fischer, Keith C.; Kibel, Adam S.; Andriole, Gerald L.; Miller, Tom R.Journal of Nuclear Medicine (2013), 54 (5), 699-706CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)Despite early detection programs, many patients with prostate cancer present with intermediate- or high-risk disease. We prospectively investigated whether 11C-acetate PET/CT predicts lymph node (LN) metastasis and treatment failure in men for whom radical prostatectomy is planned. Methods: 107 men with intermediate- or high-risk localized prostate cancer and neg. conventional imaging findings underwent PET/CT with 11C-acetate. Five underwent LN staging only, and 102 underwent LN staging and prostatectomy. PET/CT findings were correlated with pathol. nodal status. Treatment-failure-free survival was estd. by the Kaplan-Meier method. The ability of PET/CT to predict outcomes was evaluated by multivariate Cox proportional hazards anal. Results: PET/CT was pos. for pelvic LN or distant metastasis in 36 of 107 patients (33.6%). LN metastasis was present histopathol. in 25 (23.4%). The sensitivity, specificity, and pos. and neg. predictive values of PET/CT for detecting LN metastasis were 68.0%, 78.1%, 48.6%, and 88.9%, resp. Treatment failed in 64 patients: 25 with metastasis, 17 with a persistent postprostatectomy prostate-specific antigen level greater than 0.20 ng/mL, and 22 with biochem. recurrence (prostate-specific antigen level > 0.20 ng/mL after nadir) during followup for a median of 44.0 mo. Treatment-failure-free survival was worse in PET-pos. than in PET-neg. patients (P < 0.0001) and in those with false-pos. than in those with true-neg. scan results (P < 0.01), suggesting that PET may have demonstrated nodal disease not removed surgically or identified pathol. PET positivity independently predicted failure in preoperative (hazard ratio, 3.26; P < 0.0001) and postoperative (hazard ratio, 3.07; P = 0.0001) multivariate models. Conclusion: In patients planned for or completing prostatectomy, 11C-acetate PET/CT detects LN metastasis not identified by conventional imaging and independently predicts treatment-failure-free survival.
- 99Leisser, A.; Pruscha, K.; Ubl, P.; Wadsak, W.; Mayerhöfer, M.; Mitterhauser, M.; Hacker, M.; Kramer, G.; Shariat, S.; Karanikas, G.; Hartenbach, M.; Haug, A. R. Evaluation of fatty acid synthase in prostate cancer recurrence: SUV of [11C]acetate PET as a prognostic marker. Prostate 2015, 75, 1760– 1767, DOI: 10.1002/pros.23061[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFOksLnI&md5=0506e30dbe2d0a5dbac9cad86ca52a52Evaluation of fatty acid synthase in prostate cancer recurrence: SUV of [11C]acetate PET as a prognostic markerLeisser, Asha; Pruscha, Konstatin; Ubl, Philipp; Wadsak, Wolfgang; Mayerhoefer, Marius; Mitterhauser, Markus; Hacker, Marcus; Kramer, Gero; Shariat, Shahrokh; Karanikas, Georgios; Hartenbach, Markus; Haug, Alexander R.Prostate (Hoboken, NJ, United States) (2015), 75 (15), 1760-1767CODEN: PRSTDS; ISSN:0270-4137. (Wiley-Blackwell)Aim: High levels of fatty acid synthase have shown to correlate with the aggressiveness of prostate cancer. As [11C]acetate exhibits a close correlation with the level of fatty acid synthase, we aimed to assess whether the SUV in [11C]acetate PET serves as a suitable prognostic marker in patients with recurrent prostate cancer. Materials and Methods: In 123 consecutive patients, examd. between 2010 and 2014, the max. standardized uptake value (SUVmax) of local recurrences as well as lymph node and bone metastases was measured. Choosing the spleen as a std. for relatively high physiol. uptake, a ratio of tumor to spleen uptake (SUVts) was calcd. for standardizing the uptake, too. The corresponding initial Gleason scores (GS) and serum-PSA levels around the time of the performed PET/CT for each patient were retrospectively collected and PSA doubling together with PSA velocity were detd. For further anal. patients were divided with regard to their initial Gleason score (≤3 + 4 and ≥ 4 + 3). The median of PSA velocity was calcd. to sep. patients with a high and low PSA velocity and Mann-Whitney U or Student's t-test were used, testing for significant differences. For correlation Spearmen-Rho test was used. Results : PET was pos. for recurrence in 82/123 patients. PSA was significantly higher in PET-pos. than in neg. patients (5.9 vs. 3.2 ng/mL; P = 0.006). Initial Gleason score did not differ in PET neg. and pos. patients (P = 0.3), whereas PSA velocity was markedly higher in PET pos. patients (0.4 vs. 0.1 ng/mL/mo; P = 0.01). Median SUVmax of PET pos. patients was 5.23 (mean 5.78; range 0.9-16.8) and median SUVts was 0.78 (mean 0.84, range 0.14-2.50). SUVts was significantly higher in patients with high PSA velocity (SUVts 0.76 vs. 0.92; P = 0.009), whereas SUVmax failed statistical significance (5.4 vs. 6.3 ng/mL/mo; P = 0.08). Patients with a high SUVmax proved to have a significantly higher median Gleason score compared to low uptake (8.0 vs. 7.0; P = 0.004). Vice versa both SUVmax (GS 6: 5.0; GS 7: 5.6; GS 8: 5.7; GS 9: 6.5; r = 0.30, P = 0.008) and SUVts (GS 6: 0.63; GS 7: 0.68; GS 8: 0.85; GS 9: 0.89; r = 0.30, P = 0.006) significantly correlated with Gleason score. Patients with a Gleason score ≤ 3 + 4 had a significantly lower SUVmax (4.8 vs. 5.7; P = 0.02) and SUVts (0.67 vs. 0.85; P = 0.02) as compared to a Gleason score ≥ 4 + 3. Conclusion: [11C]acetate uptake demonstrated to correlate with initial Gleason score. Furthermore, patients with a high PSA velocity proved to have higher [11C]acetate uptake in tumor lesions.
- 100Dusing, R. W.; Peng, W.; Lai, S.-M.; Grado, G. L.; Holzbeierlein, J. M.; Thrasher, J. B.; Hill, J.; Van Veldhuizen, P. J. Prostate-specific antigen and prostate-specific antigen velocity as threshold indicators in 11C-Acetate PET/CTAC scanning for prostate cancer recurrence. Clinical Nuclear Medicine. 2014, 39, 777– 783, DOI: 10.1097/RLU.0000000000000516[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cbjtlKktA%253D%253D&md5=3caf04b61f8575e4c33452e5560f040fProstate-specific antigen and prostate-specific antigen velocity as threshold indicators in 11C-acetate PET/CTAC scanning for prostate cancer recurrenceDusing Reginald W; Peng Warner; Lai Sue-Min; Grado Gordon L; Holzbeierlein Jeffrey M; Thrasher J Brantley; Hill Jacqueline; Van Veldhuizen Peter JClinical nuclear medicine (2014), 39 (9), 777-83 ISSN:.PURPOSE: The aim of this study was to identify which patient characteristics are associated with the highest likelihood of positive findings on 11C-acetate PET/computed tomography attenuation correction (CTAC) (PET/CTAC) scan when imaging for recurrent prostate cancer. METHODS: From 2007 to 2011, 250 11C-acetate PET/CTAC scans were performed at a single institution on patients with prostate cancer recurrence after surgery, brachytherapy, or external beam radiation. Of these patients, 120 met our inclusion criteria. Logistic regression analysis was used to examine the relationship between predictability of positive findings and patients' characteristics, such as prostate-specific antigen (PSA) level at the time of scan, PSA kinetics, Gleason score, staging, and type of treatment before scan. RESULTS: In total, 68.3% of the 120 11C-acetate PET/CTAC scans were positive. The percentage of positive scans and PSA at the time of scanning and PSA velocity (PSAV) had positive correlations. The putative sensitivity and specificity were 86.6% and 65.8%, respectively, when a PSA level greater than 1.24 ng/mL was used as the threshold for scanning. The putative sensitivity and specificity were 74% and 75%, respectively, when a PSAV level greater than 1.32 ng/mL/y was used as the threshold. No significant associations were found between scan positivity and age, PSA doubling time, Gleason score, staging, or type of treatment before scanning. CONCLUSIONS: This retrospective study suggests that threshold models of PSA greater than 1.24 ng/mL or PSAV greater than 1.32 ng/mL per year are independent predictors of positive findings in 11C-acetate PET/CTAC imaging of recurrent prostate cancer.
- 101Yamamoto, Y.; Nishiyama, Y.; Kimura, N.; Kameyama, R.; Kawai, N.; Hatakeyama, T.; Kaji, M.; Ohkawa, M. 11C-acetate PET in the evaluation of brain glioma: Comparison with 11C-methionine and 18F-FDG-PET. Mol. Imaging Biol. 2008, 10, 281– 287, DOI: 10.1007/s11307-008-0152-5[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cvpvVygtQ%253D%253D&md5=99af6ee173c61346e47b54d73546e7cb11C-acetate PET in the evaluation of brain glioma: comparison with 11C-methionine and 18F-FDG-PETYamamoto Y; Nishiyama Y; Kimura N; Kameyama R; Kawai N; Hatakeyama T; Kaji M; Ohkawa MMolecular imaging and biology (2008), 10 (5), 281-7 ISSN:1536-1632.PURPOSE: The aim of the study is to retrospectively investigate the usefulness of 11C-acetate (ACE)-positron emission tomography (PET) for evaluation of brain glioma, in comparison with 11C-methionine (MET) and 2-deoxy-2-18F-fluoro-D-glucose (FDG). PROCEDURES: Fifteen patients with brain glioma referred to initial diagnosis were examined with ACE, MET, and FDG-PET. Five patients had low-grade gliomas (grade II), three had anaplastic astrocytomas (grade III), and seven had glioblastomas (grade IV). PET results were evaluated by visual and semiquantitative analysis. For semiquantitative analysis, the standardized uptake value (SUV) and tumor to contralateral normal gray matter (T/N) ratio were calculated. The sensitivity for detection of high-grade gliomas was calculated using visual analysis. RESULTS: Sensitivities of ACE, MET, and FDG were 90%, 100%, and 40%, respectively. ACE and MET T/N ratios were significantly higher than that of FDG. ACE and FDG SUV in high-grade gliomas were significantly higher than that in low-grade gliomas. No significant differences were observed using MET. CONCLUSIONS: ACE PET is a potentially useful radiotracer for detecting brain gliomas and differentiating high-grade gliomas.
- 102Tsuchida, T.; Takeuchi, H.; Okazawa, H.; Tsujikawa, T.; Fujibayashi, Y. Grading of brain glioma with 1–11C-acetate PET: Comparison with 18F-FDG PET. Nucl. Med. Biol. 2008, 35, 171– 176, DOI: 10.1016/j.nucmedbio.2007.11.004[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsl2hurw%253D&md5=263040fa88e157272910a38445bf81acGrading of brain glioma with 1-11C-acetate PET: comparison with 18F-FDG PETTsuchida, Tatsuro; Takeuchi, Hiroaki; Okazawa, Hidehiko; Tsujikawa, Tetsuya; Fujibayashi, YasuhisaNuclear Medicine and Biology (2008), 35 (2), 171-176CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)The objective of this study is to reevaluate the clin. significance of 1-11C-acetate (ACE) positron emission tomog. (PET) in patients with brain glioma, in comparison with 18F-fluorodeoxyglucose (FDG) PET. Methods: Ten patients with histol. proven glioma were included in this study. They underwent PET examn. with both FDG and ACE on sep. days. For ACE PET, 20-min data acquisition was performed just after the administration of 740 MBq of ACE; 10-20-min data were used for the anal. FDG PET data acquisition for 10 min started 60 min postinjection of 370 MBq of FDG, approx. Both reconstructed images were converted to standardized uptake value (SUV) images for patient body wt. and injected dose. Regions of interest were placed on the tumor and the contralateral cerebral cortex, and SUV and tumor-to-cortex ratio (T/C) were calcd.; these values were compared between high- and low-grade gliomas. Results: SUV and T/C of ACE PET showed significant difference (SUV: 2.63±0.46 vs. 1.85±0.56, P =.03; T/C: 2.36±0.63 vs. 1.14±0.36, P =.02). In contrast, FDG PET revealed no significant difference in SUV or T/C between high- and low-grade gliomas (SUV: 7.13±4.31 vs. 4.71±1.27, P =.31; T/C: 0.98±0.55 vs. 0.62±0.09, P =.22). Conclusion: This preliminary study revealed that ACE PET is a promising tracer for the grading of brain glioma.
- 103Kim, S.; Kim, D.; Kim, S. H.; Park, M.; Chang, J. H.; Yun, M. The roles of 11C-acetate PET/CT in predicting tumor differentiation and survival in patients with cerebral glioma. Eur. J. Nucl. Med. Mol. Imaging 2018, 45, 1012– 1020, DOI: 10.1007/s00259-018-3948-9[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MrosVSntw%253D%253D&md5=a6a6c103f8e0de500f6bb0f910ba47a3The roles of (11)C-acetate PET/CT in predicting tumor differentiation and survival in patients with cerebral gliomaKim Soyoung; Kim Dongwoo; Yun Mijin; Kim Se Hoon; Park Mi-Ae; Chang Jong HeeEuropean journal of nuclear medicine and molecular imaging (2018), 45 (6), 1012-1020 ISSN:.PURPOSE: This prospective study aimed to evaluate the clinical values of (11)C-acetate positron emission tomography/computed tomography (PET/CT) in predicting histologic grades and survival in patients with cerebral glioma. METHODS: Seventy-three patients with surgically confirmed cerebral gliomas (19 grade II, 21 grade III, and 33 grade IV) who underwent (11)C-acetate PET/CT before surgery were included. Tumor-to-choroid plexus ratio (TCR), which was defined as the maximum standardized uptake value (SUV) of tumors to the mean SUV of choroid plexus, was compared between three World Health Organization (WHO) grade groups. Moreover, metabolic tumor volumes (MTV) were calculated. Progression-free survival (PFS) and overall survival (OS) curves were plotted using the Kaplan-Meier method, and differences in survival between groups were assessed using the log-rank test. RESULTS: Median TCR was 1.20 (interquartile range [IQR], 1.14 to 1.4) in grade II, 1.65 (IQR, 1.26 to 1.79) in grade III, and 2.53 (IQR, 1.93 to 3.30) in grade IV gliomas. Significant differences in TCR were seen among the three WHO grade groups (P < 0.001). In Cox regression analysis including TCR, MTV, molecular markers, and other clinical factors, TCR was prognostic for PFS (P = 0.016) and TCR and MTV were prognostic for OS (P = 0.024 [TCR], P = 0.030 [MTV]). PFS and OS were significantly shorter in patients with a TCR ≥ 1.6 than in those with a TCR < 1.6. OS were significantly shorter in patients with a MTV ≥ 1 than in those with a TCR < 1. CONCLUSIONS: TCR on (11)C-acetate PET/CT significantly differed between low- and high-grade cerebral gliomas, and it showed the capability to further differentiate grade III from grade IV tumors. TCR and MTV were independent prognostic factors and predicted survival better than did the WHO grade.
- 104Christman, D.; Crawford, E. J.; Friedkin, M.; Wolf, A. P. Detection of DNA synthesis in intact organisms with positron-emitting [methyl-11C]thymidine. Proc. Natl. Acad. Sci. U. S. A. 1972, 69, 988– 992, DOI: 10.1073/pnas.69.4.988[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38XktVanurc%253D&md5=95954ed3e383e2f46bf41c99f0715817Detection of DNA synthesis in intact organisms with positron-emitting [methyl-11C]-thymidineChristman, David; Crawford, Elizabeth J.; Friedkin, Morris; Wolf, Alfred P.Proceedings of the National Academy of Sciences of the United States of America (1972), 69 (4), 988-92CODEN: PNASA6; ISSN:0027-8424.1CO2 produced in the Brookhaven 152-cm cyclotron was converted to CH2O, which in turn was used for the enzymic conversion of deoxyuridine-5'-phosphate to thymidylate-11C (I). Enzymic treatment of the nucleotide with alk. phosphatase gave thymidine-11C (II). The prepn. of II from cyclotron-generated 11CO2 required 110 min (about 5 half-lives): 35 min for the synthesis of 11CH2O, 25 min for the enzymic conversion to I, 20 min for column chromatog., 5 min for phosphatase treatment, 10 min for evapn., 2 min for filtration through an anion-exchange resin, and 13 min for misc. manipulations. Positron-emitting II and I were used for in vivo tracer studies of DNA synthesis in mice for periods of up to 3 hr. Findings with 11C were consistent with earlier studies in which 14C and 3H-labeled thymidine were used.
- 105Wells, P.; Gunn, R. N.; Alison, M.; Steel, C.; Golding, M.; Ranicar, A. S.; Brady, F.; Osman, S.; Jones, T.; Price, P. Assessment of proliferation in vivo using 2-[(11)C]thymidine positron emission tomography in advanced intra-abdominal malignancies. Cancer Res. 2002, 62, 5698– 5702[PubMed], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotFyksbo%253D&md5=53aab8620638a24d9ad0351c7d23f1bcAssessment of proliferation in vivo using 2-[11C]thymidine positron emission tomography in advanced intra-abdominal malignanciesWells, Paula; Gunn, Roger N.; Alison, Malcolm; Steel, Colin; Golding, Mathew; Ranicar, Alex S.; Brady, Frank; Osman, Safiye; Jones, Terry; Price, PatCancer Research (2002), 62 (20), 5698-5702CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The purpose of this study was to det. the relationship between 2-[11C]thymidine positron emission tomog. (PET) in vivo-derived parameters and the ex vivo Ki-67 index of proliferation in human tumors. The study comprised 17 treatment-naive patients with advanced intra-abdominal malignancies. Tumor thymidine kinetics were measured using 2-[11C]thymidine PET. Tissue data were analyzed to give the standardized uptake value, the area under the time activity curve, and the fractional retention of thymidine (FRT) obtained by kinetic modeling. For the latter, the contribution of labeled metabolites was accounted for by measuring thymidine metabolites in arterial plasma. To examine the influence of tumor blood flow on the thymidine PET data, a perfusion scan using inhaled [15O]CO2 was carried out in a subset of 11 patients. Biopsies were stained with a MIB1 antibody to obtain a Ki-67 index, and correlations with the PET-derived parameters were investigated. There was no relationship between tumor blood flow and the thymidine PET data, showing that the retention of 2-[11C]thymidine in tumors was independent of tumor perfusion. There was no correlation between the Ki-67 index and either std. uptake value or area under the curve. There was a correlation between the Ki-67 index and FRT (r = 0.58; P = 0.01). The correlation between the Ki-67 index and FRT in this dataset was not influenced by the interval between biopsy and imaging (0.1-126 wk), the origin of the biopsy for Ki-67 staining (primary tumor or metastasis), or whether the biopsy was from an imaged or a nonimaged tumor. This is the first report in human tumors showing that 2-[11C]thymidine PET-derived parameters correlate with the level of tumor proliferation measured using Ki-67 immunohistochem. The study shows that the in vivo measurement of 2-[11C]thymidine in tumors using PET can provide a surrogate marker of proliferation and supports the potential use of the technique in the early assessment of response to antiproliferative cancer treatment.
- 106Barwick, T.; Bencherif, B.; Mountz, J. M.; Avril, N. Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: A comprehensive evaluation. Nucl. Med. Commun. 2009, 30, 908– 917, DOI: 10.1097/MNM.0b013e32832ee93b[Crossref], [PubMed], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1SltbnL&md5=5e4c6c8a38cd0e0577d78e85c769ba5dMolecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluationBarwick, Tara; Bencherif, Badreddine; Mountz, James M.; Avril, NorbertNuclear Medicine Communications (2009), 30 (12), 908-917CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)A review. Positron emission tomog. (PET) using F-18 fluoro-3'-deoxy-3-L-fluorothymidine (FLT) offers noninvasive assessment of cell proliferation in vivo. The most important application refers to the evaluation of tumor proliferative activity, representing a key feature of malignancy. Most data to date suggest that FLT is not a suitable biomarker for staging of cancers. This is because of the rather low fraction of tumor cells that undergo replication at a given time with subsequently relatively low tumor FLT uptake. In addn., generally, the high FLT uptake in liver and bone marrow limits the diagnostic use. We describe the current status on preclin. and clin. applications of FLT-PET including our own experience in brain tumors. The future of FLT-PET probably lies in the evaluation of tumor response to therapy and more importantly, in the prediction of early response in the course of treatment. The level of FLT accumulation in tumors depends on thymidine kinase 1 activity and on the therapy-induced activation of the salvage pathway and expression of nucleoside transporters. Therefore, cytostatic agents that cause arrest of the cell cycle in the S-phase may initially increase FLT uptake rather than reducing the tumor cell accumulation. In addn., agents that block the endogenous thymidine pathway may lead to overactivity of the salvage pathway and increase tumor FLT uptake. In contrast, many therapeutic agents inhibit both pathways and subsequently reduce tumor FLT uptake. Further studies comparing FLT with F-18 fluorodeoxyglucose-PET will be important to det. the complementary advantage of FLT-PET in early cancer therapy response assessment. Further research should be facilitated by simplified synthesis of FLT with improved yields and an increasing com. availability.
- 107Conti, P. S.; Alauddin, M. M.; Fissekis, J. R.; Schmall, B.; Watanabe, K. A. Synthesis of 2′-fluoro-5-[11C]-methyl-1-β-d-arabinofuranosyluracil ([11C]-FMAU): A potential nucleoside analog for in vivo study of cellular proliferation with PET. Nucl. Med. Biol. 1995, 22, 783– 789, DOI: 10.1016/0969-8051(95)00017-R[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXos1ChsLw%253D&md5=3a594ac09c35247304ebc6e2f763eb492'-fluoro-5-[11C]-methyl-1-β-d-arabinofuranosyluracil ([11C]-FMAU): a potential nucleoside analog for in vivo study of cellular proliferation with PETConti, Peter S.; Alauddin, Mian M.; Fissekis, John R.; Schmall, Bernard; Watanabe, Kyochi A.Nuclear Medicine and Biology (1995), 22 (6), 783-9CODEN: NMBIEO; ISSN:0883-2897. (Elsevier)Rapid in vivo catabolism limits the use of currently available radiotracers used in tumor proliferation studies with positron emission tomog. (PET). This is manifested by the need to develop complex math. models to interpret kinetic and metabolite data obtained from imaging studies with agents such as carbon-11 labeled thymidine. A potential carbon-11 labeled radiotracer for cellular proliferation, 2'-fluoro-5-([11C]-methyl)-1-β-D-arabinofuranosyluracil (FMAU), has been prepd. using a previously described method for prepn. of [11C]methyl-thymidine where selective alkylation of a pyrimidyl dianion is accomplished with [11C]methyl iodide at the 5-position of the pyrimidine ring. FMAU shares many in vivo characteristics of thymidine, including cellular transport, phosphorylation by mammalian kinase, and incorporation into DNA. Most importantly, in vivo catabolism of FMAU is limited, potentially yielding simplified kinetic models for detn. of cellular proliferation with positron emission tomog.
- 108Conti, P. S.; Bading, J. R.; Mouton, P. P.; Links, J. M.; Alauddin, M. M.; Fissekis, J. D.; Ravert, H. T.; Hilton, J.; Wong, D. F.; Anderson, J. H. In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET. Nucl. Med. Biol. 2008, 35, 131– 141, DOI: 10.1016/j.nucmedbio.2007.09.003[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVOlt7zO&md5=4189b8f346ad659be7b4414204443605In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PETConti, Peter S.; Bading, James R.; Mouton, Peter P.; Links, Jonathan M.; Alauddin, Mian M.; Fissekis, John D.; Ravert, Hayden T.; Hilton, John; Wong, Dean F.; Anderson, James H.Nuclear Medicine and Biology (2008), 35 (1), 131-141CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)Introduction: Noncatabolized thymidine analogs are being developed for use in imaging DNA synthesis. We sought to relate a labeling index measured by immunohistochem. staining bromodeoxyuridine (BUdR) technique to the uptake of 11C 2'-fluoro-5-methyl-1-β-D-arabinofuranosyluracil (FMAU) measured with positron emission tomog. (PET) in a brain tumor model. Methods: Adult beagles (n = 8) with implanted brain tumors received [11C]FMAU and dynamic imaging with arterial sampling. Six dogs were then infused with BUdR (200 mg/m2) and sacrificed. Tumor time-activity curves (TACs) obtained from computed-tomog.-defined regions of interest were cor. for partial vol. effects and crosstalk from brain tissue. Tissue was analyzed for the percentage of tumor vol. occupied by viable cells and by viable cells in S-phase as identified by BUdR staining. PET/[11C]FMAU and BUdR were compared by linear regression anal. and anal. of variance, as well as by a nonparametric rank correlation test. Results: Tumor standardized uptake values (SUVs) and tumor-to-contralateral-brain uptake ratios at 50 min were 1.6±0.4 and 5.5±1.2 (n = 8; mean ± S.E.M.), resp. No 11C-labeled metabolites were obsd. in the blood through 60 min. Tumor TACs were well described with a three-compartment/four-parameter model (k4 = 0) and by Patlak anal. Parametric statistical anal. showed that FMAU clearance from plasma into tumor compartment 3 (KFMAU) was significantly correlated with S-phase percent vol. (P =.03), while tumor SUV was significantly correlated with both S-phase percent vol. and cell percent vol. (P =.02 and.03, resp.). Patlak slope, KFMAU and tumor SUV were equiv. with regard to rank correlation anal., which showed that tumor uptake and trapping of FMAU were correlated with the vol. d. of dividing cells (P =.0003) rather than nondividing cells (P =.3). Conclusions: Trapping of [11C]FMAU correlated with tumor growth rate, as measured by direct tissue anal. with BUdR in a canine brain tumor model, suggesting that [11C]FMAU is useful for the imaging of cell proliferation in cancers.
- 109Shields, A. F. PET imaging with 18F-FLT and thymidine analogs: Promise and pitfalls. J. Nucl. Med. 2003, 44, 1432– 1434[PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVSrt74%253D&md5=fdffb85db8a9f44c9aef7da723df9e46PET imaging with 18F-FLT and thymidine analogs: promise and pitfallsShields, Anthony F.Journal of Nuclear Medicine (2003), 44 (9), 1432-1434CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review on imaging of cellular proliferation in tumors with 18F-labeled 3'-deoxy-3'fluorothymidine (18F-FLT) and thymidine analogs using positron emission tomog. (PET).
- 110Toyohara, J. Evaluation of DNA synthesis with carbon-11-labeled 4′-thiothymidine. WJR. 2016, 8, 799– 808, DOI: 10.4329/wjr.v8.i9.799
- 111Nariai, T.; Inaji, M.; Sakata, M.; Toyohara, J. Use of 11C-4DST-PET for Imaging of Human Brain Tumors. In Tumors of the Central Nervous System, Vol. 11; Hayat, M. A., Ed.; Tumors of the Central Nervous System; Springer Netherlands: Dordrecht, The Netherlands, 2014; Vol. 11, pp 41– 48.
- 112Toyota, Y.; Miyake, K.; Kawai, N.; Hatakeyama, T.; Yamamoto, Y.; Toyohara, J.; Nishiyama, Y.; Tamiya, T. Comparison of 4′-[methyl-11C]thiothymidine (11C-4DST) and 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) PET/CT in human brain glioma imaging. EJNMMI Res. 2015, 5, 7, DOI: 10.1186/s13550-015-0085-3[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mjit1Wjug%253D%253D&md5=ebb2a3b02785d5e9875738c1f09abdc1Comparison of 4'-[methyl-(11)C]thiothymidine ((11)C-4DST) and 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) PET/CT in human brain glioma imagingToyota Yasunori; Miyake Keisuke; Kawai Nobuyuki; Hatakeyama Tetsuhiro; Tamiya Takashi; Yamamoto Yuka; Nishiyama Yoshihiro; Toyohara JunEJNMMI research (2015), 5 (), 7 ISSN:2191-219X.BACKGROUND: 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) has been used to evaluate tumor malignancy and cell proliferation in human brain gliomas. However, (18)F-FLT has several limitations in clinical use. Recently, (11)C-labeled thymidine analogue, 4'-[methyl-(11)C]thiothymidine ((11)C-4DST), became available as an in vivo cell proliferation positron emission tomography (PET) tracer. The present study was conducted to evaluate the usefulness of (11)C-4DST PET in the diagnosis of human brain gliomas by comparing with the images of (18)F-FLT PET. METHODS: Twenty patients with primary and recurrent brain gliomas underwent (18)F-FLT and (11)C-4DST PET scans. The uptake values in the tumors were evaluated using the maximum standardized uptake value (SUVmax), the tumor-to-normal tissue uptake (T/N) ratio, and the tumor-to-blood uptake (T/B) ratio. These values were compared among different glioma grades. Correlation between the Ki-67 labeling index and the uptake values of (11)C-4DST and (18)F-FLT in the tumor was evaluated using linear regression analysis. The relationship between the individual (18)F-FLT and (11)C-4DST uptake values in the tumors was also examined. RESULTS: (11)C-4DST uptake was significantly higher than that of (18)F-FLT in the normal brain. The uptake values of (11)C-4DST in the tumor were similar to those of (18)F-FLT resulting in better visualization with (18)F-FLT. No significant differences in the uptake values of (18)F-FLT and (11)C-4DST were noted among different glioma grades. Linear regression analysis showed a significant correlation between the Ki-67 labeling index and the T/N ratio of (11)C-4DST (r = 0.50, P < 0.05) and (18)F-FLT (r = 0.50, P < 0.05). Significant correlations were also found between the Ki-67 labeling index and the T/B ratio of (11)C-4DST (r = 0.52, P < 0.05) and (18)F-FLT (r = 0.55, P < 0.05). A highly significant correlation was observed between the individual T/N ratio of (11)C-4DST and (18)F-FLT in the tumor (r = 0.79, P = 0.0001). CONCLUSIONS: The present study demonstrates that (11)C-4DST is useful for the imaging of human brain gliomas with PET. A relatively higher background uptake of (11)C-4DST in the normal brain compared to (18)F-FLT limits the detection of low-tracer-uptake tumors. Moreover, no superiority was found in (11)C-4DST over (18)F-FLT in the evaluation of cell proliferation.
- 113Tanaka, K.; Yamamoto, Y.; Maeda, Y.; Yamamoto, H.; Kudomi, N.; Kawai, N.; Toyohara, J.; Nishiyama, Y. Correlation of 4′-[methyl-11C]-thiothymidine uptake with Ki-67 immunohistochemistry and tumor grade in patients with newly diagnosed gliomas in comparison with 11C-methionine uptake. Ann. Nucl. Med. 2016, 30, 89– 96, DOI: 10.1007/s12149-015-1035-x[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslersr7J&md5=66a526982a6b5b762c23608a3f9bae78Correlation of 4'-[methyl-11C]-thiothymidine uptake with Ki-67 immunohistochemistry and tumor grade in patients with newly diagnosed gliomas in comparison with 11C-methionine uptakeTanaka, Kenichi; Yamamoto, Yuka; Maeda, Yukito; Yamamoto, Hiroyuki; Kudomi, Nobuyuki; Kawai, Nobuyuki; Toyohara, Jun; Nishiyama, YoshihiroAnnals of Nuclear Medicine (2016), 30 (2), 89-96CODEN: ANMEEX; ISSN:0914-7187. (Springer Japan)A novel radiopharmaceutical, 4'-[methyl-11C]thiothymidine (11C-4DST), has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate 11C-4DST uptake in patients with newly diagnosed glioma and to correlate the results with proliferative activity and tumor grade, in comparison with L-[methyl-11C]-methionine (11C-MET). Investigations of 11C-4DST and 11C-MET PET/CT were performed retrospectively in 23 patients with newly diagnosed glioma. The max. standardized uptake value (SUVmax) for tumor (T) and the mean SUV for normal contralateral hemisphere (N) were calcd., and the tumor-to-normal (T/N) ratio was detd. Metabolic tumor vol. (MTV) was defined as the vol. with a threshold of 40% of the SUVmax. Proliferative activity as indicated by the Ki-67 index was estd. in tissue specimens. Of 23 gliomas examd., 11C-4DST PET/CT and 11C-MET PET/CT detected 20 and 22, resp. Linear regression anal. between 11C-4DST and 11C-MET indicated a weak correlation for SUVmax (r = 0.54, P < 0.008), for T/N ratio (r = 0.56, P < 0.006), and for MTV (r = 0.60, P < 0.003). Linear regression anal. indicated a weak correlation between 11C-4DST and Ki-67 index for SUVmax (r = 0.46, P < 0.03), for T/N ratio (r = 0.43, P < 0.05), and for MTV (r = 0.68, P < 0.001) and between 11C-MET MTV and Ki-67 index (r = 0.43, P < 0.04). Using 11C-4DST, there was a significant difference in SUVmax between grades II and IV (P < 0.03) and in MTV between grades II and IV (P < 0.009) and grades III and IV (P < 0.02). Using 11C-MET, there was a significant difference in SUVmax (P < 0.009) and T/N ratio (P < 0.02) between grades II and IV and in MTV between grades II and IV (P < 0.03) and grades III and IV (P < 0.02). A11C-4DST PET/CT is feasible for imaging of brain gliomas, as well as 11C-MET PET/CT. Esp., it showed the highest correlation coeff. between 11C-4DST MTV and Ki-67 index in newly diagnosed gliomas.
- 114Ito, K.; Yokoyama, J.; Miyata, Y.; Toyohara, J.; Okasaki, M.; Minamimoto, R.; Morooka, M.; Ishiwata, K.; Kubota, K. Volumetric comparison of positron emission tomography/computed tomography using 4′-[methyl-11C]-thiothymidine with 2-deoxy-2–18F-fluoro-D-glucose in patients with advanced head and neck squamous cell carcinoma. Nucl. Med. Commun. 2015, 36, 219– 225, DOI: 10.1097/MNM.0000000000000241[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVOhtr4%253D&md5=a7943d28c1676d2e2b65f338fdff54ecVolumetric comparison of positron emission tomography/computed tomography using 4'-[methyl-11C]-thiothymidine with 2-deoxy-2-18F-fluoro-D-glucose in patients with advanced head and neck squamous cell carcinomaIto, Kimiteru; Yokoyama, Junkichi; Miyata, Yoko; Toyohara, Jun; Okasaki, Momoko; Minamimoto, Ryogo; Morooka, Miyako; Ishiwata, Kiichi; Kubota, KazuoNuclear Medicine Communications (2015), 36 (3), 219-225CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)Objective: We prospectively compared the diagnostic value of PET/computed tomog. (CT) findings using the tracers 4'-[methyl-C]-thiothymidine (C-4DST) and 2-deoxy-2-F-fluoro-D-glucose (F-FDG) in patients with head and neck squamous cell carcinoma (HNSCC). Patients and methods: Thirty-eight patients with advanced HNSCC underwent C-4DST PET/CT and F-FDG PET/CT before treatment. Maximum standardized uptake values (SUVmax) were measured for both PET/CT studies; in addn., total lesion glycolysis (TLG) of F-FDG PET/CT and total lesion proliferation (TLP) of C-4DST PET/CT were measured. Abs. TLG and TLP values as well as values with various SUV thresholds were measured. All patients were followed up for 13.5±7.5 mo (mean±SD) to monitor recurrence. Results: A statistically significant correlation was obsd. between the primary tumor SUVmax for C-4DST PET/CT and F-FDG PET/CT (r=0.46, P<0.01). TLP values with SUV thresholds strongly correlated with TLG values relative to the same thresholds (r=0.60-0.92, P<0.001). Nine of the 38 patients with post-treatment recurrence were identified. Receiver operating characteristic curves for TLG3.0 and TLP2.5 showed the highest prognostic ability for recurrence; the sensitivity and specificity of TLG3.0 were 89 and 72%, resp., and the sensitivity and specificity of TLP2.5 were 89 and 55%, resp. Conclusion: In patients with advanced HNSCC, the TLP of C-4DST PET/CT strongly correlated with the TLG of F-FDG PET/CT. Although there were no large differences between these values, the receiver operating characteristic curves of the abs. TLG had slightly better prognostic ability for recurrence.
- 115Minamimoto, R.; Toyohara, J.; Ito, H.; Seike, A.; Miyata, Y.; Morooka, M.; Okasaki, M.; Nakajima, K.; Ito, K.; Ishiwata, K.; Kubota, K. A pilot study of 4′-[methyl-11C]-thiothymidine PET/CT for detection of regional lymph node metastasis in non-small cell lung cancer. EJNMMI Res. 2014, 4, 10, DOI: 10.1186/2191-219X-4-10[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crgslKhsA%253D%253D&md5=1e53d6912c4225449e09a2dbb3ebaf32A pilot study of 4'-[methyl-11C]-thiothymidine PET/CT for detection of regional lymph node metastasis in non-small cell lung cancerMinamimoto Ryogo; Toyohara Jun; Ito Hideyuki; Seike Ayako; Miyata Yoko; Morooka Miyako; Okasaki Momoko; Nakajima Kazuhiko; Ito Kimiteru; Ishiwata Kiichi; Kubota KazuoEJNMMI research (2014), 4 (1), 10 ISSN:2191-219X.BACKGROUND: 4'-[methyl-11C]-thiothymidine (4DST) is a novel positron emission tomography (PET) tracer to assess proliferation of malignancy. The diagnostic abilities of 4DST and 2-deoxy-2-18 F-fluoro-d-glucose (FDG) for detecting regional lymph node (LN) metastases of non-small cell lung cancer (NSCLC) were prospectively compared. In addition, the relationship between the PET result and the patient's prognosis was evaluated. METHODS: A total of 31 patients with NSCLC underwent 4DST PET/computed tomography (CT) and FDG PET/CT. The PET/CT images were evaluated qualitatively and quantitatively for focal uptake of each PET tracer, according to the staging system of the American Joint Committee on Cancer. Surgical and histological results provided the reference standards. Patients were followed for up to two years to assess disease-free survival. RESULTS: On a per-lesion basis, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for LN staging were 82%, 72%, 32%, 96%, and 73%, respectively, for 4DST, and 29%, 86%, 25%, 88%, and 78%, respectively, for FDG. The sensitivity of 4DST was significantly higher than that of FDG (P < 0.001). The disease-free survival rate with positive 4DST uptake in nodal lesions was 0.35, which was considerably lower than the rate of 0.83 with negative findings (P = 0.04). Among the factors tested, nodal staging by 4DST was the most influential prognostic factor (P = 0.05) in predicting the presence of a previously existing spread lesion or of a recurrence over the course of 2 years. CONCLUSION: 4DST PET/CT is sensitive for detecting mediastinal lymph node metastasis in NSCLC, but its low specificity is a limitation. However, it may be helpful in predicting the prognosis of NSCLC.
- 116Okasaki, M.; Kubota, K.; Minamimoto, R.; Miyata, Y.; Morooka, M.; Ito, K.; Ishiwata, K.; Toyohara, J.; Inoue, T.; Hirai, R.; Hagiwara, S.; Miwa, A. Comparison of 11C-4′-thiothymidine, 11C-methionine, and 18F-FDG PET/CT for the detection of active lesions of multiple myeloma. Ann. Nucl. Med. 2015, 29, 224– 232, DOI: 10.1007/s12149-014-0931-9[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFyjsb%252FJ&md5=cfb8e29285ae78b8734444285dc445ceComparison of 11C-4'-thiothymidine, 11C-methionine, and 18F-FDG PET/CT for the detection of active lesions of multiple myelomaOkasaki, Momoko; Kubota, Kazuo; Minamimoto, Ryogo; Miyata, Yoko; Morooka, Miyako; Ito, Kimiteru; Ishiwata, Kiichi; Toyohara, Jun; Inoue, Tomio; Hirai, Risen; Hagiwara, Shotaro; Miwa, AkiyoshiAnnals of Nuclear Medicine (2015), 29 (3), 224-232CODEN: ANMEEX; ISSN:0914-7187. (Springer Japan)Purpose: The aims of this study were to evaluate the possibility of using 11C-methionine (11C-MET) and 11C-4'-thiothymidine (11C-4DST) whole-body PET/CT for the imaging of amino acid metab. and DNA synthesis, resp., when searching for bone marrow involvement in patients with multiple myeloma (MM) and to compare these findings with those for 18F-FDG PET/CT and aspiration cytol. Methods: A total of 64 patients with MM, solitary plasmacytoma, monoclonal gammopathy of undetd. significance, or an unspecified diagnosis were prospectively enrolled. All the patients underwent three whole-body PET/CT examns. within a period of 1 wk. First, the tracer accumulation was visually evaluated as pos., equivocal, or neg. for 55 focal lytic lesions visualized using CT in 24 patients. Second, the percentages of marrow plasma cells as calcd. using a bone marrow aspiration smear and tracer accumulation were evaluated in the posterior iliac crests of 36 patients. Results: Among the 55 lytic lesions, the 11C-MET and 11C-4DST findings tended to reveal more pos. findings than the 18F-FDG findings. Based on the std. criteria for the diagnosis of active myeloma using the percentage of marrow plasma cells, significant differences were found between the 18F-FDG and 11C-MET findings and between the 18F-FDG and 11C-4DST findings, but no significant difference was obsd. between the 11C-MET and 11C-4DST findings. Conclusion: The addn. of 11C-MET and 11C-4DST to 18F-FDG when performing PET/CT enabled clearer evaluations of equivocal lesions. Based on cytol. diagnostic criteria, 11C-MET and 11C-4DST were more sensitive than 18F-FDG for the detection of active lesions. 11C-MET and 11C-4DST were more useful than 18F-FDG for the detection of active lesions, esp. during the early stage of disease.
- 117Minamimoto, R.; Nakaigawa, N.; Nagashima, Y.; Toyohara, J.; Ueno, D.; Namura, K.; Nakajima, K.; Yao, M.; Kubota, K. Comparison of 11C-4DST and 18F-FDG PET/CT imaging for advanced renal cell carcinoma: Preliminary study. Abdom Radiol. 2016, 41, 521– 530, DOI: 10.1007/s00261-015-0601-y[Crossref], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fmsFelsQ%253D%253D&md5=8f36459bb884ffd39e6d6fada28cf56aComparison of 11C-4DST and 18F-FDG PET/CT imaging for advanced renal cell carcinoma: preliminary studyMinamimoto Ryogo; Nakajima Kazuhiko; Kubota Kazuo; Nakaigawa Noboru; Ueno Daiki; Namura Kazuhiro; Yao Masahiro; Nagashima Yoji; Toyohara JunAbdominal radiology (New York) (2016), 41 (3), 521-30 ISSN:.PURPOSE: 4'-[Methyl-(11)C]-thiothymidine (4DST) has been developed as an in vivo cell proliferation marker based on its DNA incorporation mechanism. This study evaluated the potential of 4DST PET/CT for imaging cellular proliferation in advanced clear cell renal cell carcinoma (RCC), compared with FDG PET/CT. Both 4DST and FDG uptake were compared with biological findings based on surgical pathology. METHODS: Five patients (3 men and 2 women; mean (±SD) age 64.8 ± 11.0 years) with a single RCC (mean diameter: 9.3 ± 3.2 cm) were examined by PET/CT using 4DST and FDG. The dynamic emission scan of 4DST for RCC over 35 min followed by a static emission scan of the body for 4DST and FDG. Then we compared the maximum standardized uptake value (SUVmax) of 20 areas of RCC on both 4DST and FDG images with (1) the Ki-67 index of cellular proliferation (2) Fuhrman grade system for nuclear grade (G) in RCC and (3) pathological phosphorylated grade of mammalian target of rapamycin (pmTOR). RESULTS: All patient cases showed clear uptake of FDG and 4DST in RCC tumors, with mean 4DST SUVmax of 7.3 ± 2.2 (range 4.3-9.4) and mean FDG SUVmax of 6.0 ± 2.8 (range 3.4-10.4). The correlation coefficient between SUVmax and Ki-67 index was higher with 4DST (r = 0.61) than with FDG (r = 0.43). Tumor 4DST uptake (G0: 1.4, G2: 2.6, G2 5.6, G4: 5.7) and tumor FDG uptake (G0: 1.8, G2: 2.9, G2 3.7, G4: 4.1) were both related to Fuhrman grade system. The 4DST uptake increased as the pmTOR grade increases (G0: 3.1, G1: 4.8, G2: 4.7, G3: 6.2); in contrast FDG uptake was unrelated to pmTOR grade (G0: 2.8, G2: 4.0, G2 3.3, G4: 3.6). CONCLUSION: A higher correlation with the proliferation of RCC was observed for 4DST than for FDG. The 4DST uptake exhibits the possibility to predict pmTOR grade, indicating that 4DST has potential for the evaluation of therapeutic effect with mTOR inhibitor in patients with RCC.
- 118Souba, W. W.; Pacitti, A. J. Review: How amino acids get into cells: Mechanisms, models, menus, and mediators. JPEN, J. Parenter. Enteral Nutr. 1992, 16, 569– 578, DOI: 10.1177/0148607192016006569[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s7ls1Wmsg%253D%253D&md5=e90b4558405af13eb46d5c37bd99eac0How amino acids get into cells: mechanisms, models, menus, and mediatorsSouba W W; Pacitti A JJPEN. Journal of parenteral and enteral nutrition (1992), 16 (6), 569-78 ISSN:0148-6071.The bloodstream provides a readily available pool of amino acids, which can be taken up by all cells of the body to support the myriad of biochemical reactions that are essential for life. The transport of amino acids into the cytoplasm occurs via functionally and biochemically distinct amino acid transport systems that have been defined on the basis of their amino acid selectivities and physico-chemical properties. Each system presumably relates to a discrete putative membrane-bound transporter protein that resides within the cell membrane and functions to translocate the amino acid from the extracellular environment into the cytoplasm. Many of these transporters require sodium for maximal activity. The sodium-dependent model presented is consistent with "preferred random" kinetics, with sodium binding preferentially before the amino acid. The transporter acts as an enzyme that catalyzes the movement of its bound amino acid (and sodium) into the cell. In this review, the authors provide a conceptual view of the mechanism of carrier-mediated amino acid transport as well as an overview of the various models that can be used in the laboratory to study this process. In addition, the known agencies that accomplish transport and their regulation by nutrition, hormones, and other mediators of critical illness are discussed.
- 119Ganapathy, V.; Thangaraju, M.; Prasad, P. D. Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond. Pharmacol. Ther. 2009, 121, 29– 40, DOI: 10.1016/j.pharmthera.2008.09.005[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFagtrrP&md5=1bebe879f37a4a55c67424394ec65a56Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyondGanapathy, Vadivel; Thangaraju, Muthusamy; Prasad, Puttur D.Pharmacology & Therapeutics (2009), 121 (1), 29-40CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review. Tumor cells have an increased demand for nutrients; this demand is met by increased availability of nutrients through vasculogenesis and by enhanced cellular entry of nutrients through upregulation of specific transporters. This review focuses on three groups of nutrient transporters relevant to cancer: glucose transporters, lactate transporters, and amino acid transporters. Tumor cells enhance glucose uptake via induction of GLUT1 and SGLT1, and coordinate the increased entry of glucose with increased glycolysis. Since enhanced glycolysis in cancer is assocd. with lactate prodn., tumor cells must find a way to eliminate lactic acid to prevent cellular acidification. This is achieved by the upregulation of MCT4, a H+-coupled lactate transporter. In addn., the Na+-coupled lactate transporter SMCT1 is silenced in cancer. SMCT1 also transports butyrate and pyruvate, which are inhibitors of histone deacetylases. The silencing of SMCT1 occurs in cancers of a variety of tissues. Re-expression of SMCT1 in cancer cell lines leads to growth arrest and apoptosis in the presence of butyrate or pyruvate, suggesting that the transporter may function as a tumor suppressor. Tumor cells meet their amino acid demands by inducing xCT/4F2hc, LAT1/4F2hc, ASCT2, and ATB0,+. xCT/4F2hc is related primarily to glutathione status, protection against oxidative stress, and cell cycle progression, whereas the other three transporters are related to amino acid nutrition. Pharmacol. blockade of LAT1/4F2hc, xCT/4F2hc, or ATB0,+ leads to inhibition of cancer cell growth. Since tumor cells selectively regulate these nutrient transporters to support their rapid growth, these transporters have potential as drug targets for cancer therapy.
- 120Langen, K.-J.; Bröer, S. Molecular transport mechanisms of radiolabeled amino acids for PET and SPECT. J. Nucl. Med. 2004, 45, 1435– 1436[PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXosVWis78%253D&md5=c1883ec8d5b26b4e3f6507063a3c9a76Molecular transport mechanisms of radiolabeled amino acids for PET and SPECTLangen, Karl JosefJournal of Nuclear Medicine (2004), 45 (9), 1435-1436CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A polemic in response to Lahoutte et al., J Nucl Med 2004;45:1591-1596. The research of Lahoutte et al. (2004) entitled "SPECT and PET amino acid tracer influx via system L (h4F2hc-hLAT1) and its transstimulation" is reviewed with commentary and refs. Lahoutte et al. analyzed the transport mechanisms of 123I-2-iodotyrosine (2IT) and compared with those of 3-123I-iodo-α-methyl-L-tyrosine (IMT) and two fluorinated amino acids currently under consideration for PET: O-(2-18F-fluoroethyl)-L-tyrosine (FET) and 2-18F-fluoro-L-tyrosine (2FT). Expression of 4F2hc-LAT1 in Xenopus laevis oocytes shows the affinity of 2IT for LAT1 is similar to that of L-tyrosine. Transtimulation expts. have shown that the influx rate of 2IT via LAT1 is comparable to that of IMT but lower than that of 2FT. In contrast, FET influx via LAT1 as found to be poor. These expts. give interesting new insights into the variable transport characteristics of these new radiolabeled amino acids. It appears that the diagnostic potential of radiolabeled amino acids will be amplified by enlarging knowledge of the mol. mechanisms involved in the transport processes.
- 121McConathy, J.; Martarello, L.; Malveaux, E. J.; Camp, V. M.; Simpson, N. E.; Simpson, C. P.; Bowers, G. D.; Olson, J. J.; Goodman, M. M. Radiolabeled amino acids for tumor imaging with PET: Radiosynthesis and biological evaluation of 2-amino-3-[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid. J. Med. Chem. 2002, 45, 2240– 2249, DOI: 10.1021/jm010241x[ACS Full Text], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFags7Y%253D&md5=24ec44499663fdb1b8938733d89c0271Radiolabeled Amino Acids for Tumor Imaging with PET: Radiosynthesis and Biological Evaluation of 2-Amino-3-[18F]fluoro-2-methylpropanoic Acid and 3-[18F]Fluoro-2-methyl-2-(methylamino)propanoic AcidMcConathy, Jonathan; Martarello, Laurent; Malveaux, Eugene J.; Camp, Vernon M.; Simpson, Nicholas E.; Simpson, Chiab P.; Bowers, Geoffrey D.; Olson, Jeffrey J.; Goodman, Mark M.Journal of Medicinal Chemistry (2002), 45 (11), 2240-2249CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Novel radiopharmaceuticals, including amino acids, that target neoplasms through their altered metabolic states have shown promising results in preclin. and clin. studies. Two fluorinated analogs of α-aminoisobutyric acid, 2-amino-3-fluoro-2-methylpropanoic acid (FAMP) and 3-fluoro-2-methyl-2-(methylamino)propanoic acid (N-MeFAMP), have been radiolabeled with fluorine-18, characterized in amino acid uptake assays, and evaluated in vivo in normal rats and a rodent tumor model. The key steps in the syntheses of both radiotracers involved the prepn. of cyclic sulfamidate precursors. Radiosyntheses of both [18F]FAMP and [18F]N-MeFAMP via no-carrier-added nucleophilic substitution provided high yields (>78% decay-cor.) in high radiochem. purity (>99%). Amino acid transport assays using 9L gliosarcoma cells demonstrated that both compds. are substrates for the A type amino acid transport system, with [18F]N-MeFAMP showing higher specificity than [18F]FAMP for A type transport. Tissue distribution studies in normal Fischer rats and Fischer rats implanted intracranially with 9L gliosarcoma tumor cells were also performed. At 60 min postinjection, the tumor vs normal brain ratio of radioactivity was 36:1 in animals receiving [18F]FAMP and 104:1 in animals receiving [18F]N-MeFAMP. On the basis of these studies, both [18F]FAMP and [18F]N-MeFAMP are promising imaging agents for the detection of intracranial neoplasms via positron emission tomog.
- 122Baek, S.; Choi, C.-M.; Ahn, S. H.; Lee, J. W.; Gong, G.; Ryu, J.-S.; Oh, S. J.; Bacher-Stier, C.; Fels, L.; Koglin, N.; Hultsch, C.; Schatz, C. A.; Dinkelborg, L. M.; Mittra, E. S.; Gambhir, S. S.; Moon, D. H. Exploratory clinical trial of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate for imaging XC- transporter using positron emission tomography in patients with non-small cell lung or breast cancer. Clin. Cancer Res. 2012, 18, 5427– 5437, DOI: 10.1158/1078-0432.CCR-12-0214[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFSgurzK&md5=eb670c06360d47d2378abdb7c008fa80Exploratory Clinical Trial of (4S)-4-(3-[18F]fluoropropyl)-l-glutamate for Imaging xC- Transporter Using Positron Emission Tomography in Patients with Non-Small Cell Lung or Breast CancerBaek, Sora; Choi, Chang-Min; Ahn, Sei Hyun; Lee, Jong Won; Gong, Gyungyub; Ryu, Jin-Sook; Oh, Seung Jun; Bacher-Stier, Claudia; Fels, Lueder; Koglin, Norman; Hultsch, Christina; Schatz, Christoph A.; Dinkelborg, Ludger M.; Mittra, Erik S.; Gambhir, Sanjiv S.; Moon, Dae HyukClinical Cancer Research (2012), 18 (19), 5427-5437CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (BAY 94-9392, alias [18F]FSPG) is a new tracer to image xC- transporter activity with positron emission tomog. (PET). We aimed to explore the tumor detection rate of [18F]FSPG in patients relative to 2-[18F]fluoro-2-deoxyglucose ([18F]FDG). The correlation of [18F]FSPG uptake with immunohistochem. expression of xC- transporter and CD44, which stabilizes the xCT subunit of system xC-, was also analyzed. Exptl. Design: Patients with non-small cell lung cancer (NSCLC, n = 10) or breast cancer (n = 5) who had a pos. [18F]FDG uptake were included in this exploratory study. PET images were acquired following injection of approx. 300 MBq [18F]FSPG. Immunohistochem. was done using xCT- and CD44-specific antibody. Results: [18F]FSPG PET showed high uptake in the kidney and pancreas with rapid blood clearance. [18F]FSPG identified all 10 NSCLC and three of the five breast cancer lesions that were confirmed by pathol. [18F]FSPG detected 59 of 67 (88%) [18F]FDG lesions in NSCLC, and 30 of 73 (41%) in breast cancer. Seven lesions were addnl. detected only on [18F]FSPG in NSCLC. The tumor-to-blood pool standardized uptake value (SUV) ratio was not significantly different from that of [18F]FDG in NSCLC; however, in breast cancer, it was significantly lower (P < 0.05). The max. SUV of [18F]FSPG correlated significantly with the intensity of immunohistochem. staining of xC- transporter and CD44 (P < 0.01). Conclusions: [18F]FSPG seems to be a promising tracer with a relatively high cancer detection rate in patients with NSCLC. [18F]FSPG PET may assess xC- transporter activity in patients with cancer. Clin Cancer Res; 18(19); 5427-37. ©2012 AACR.
- 123Huang, C.; McConathy, J. Fluorine-18 labeled amino acids for oncologic imaging with positron emission tomography. Curr. Top. Med. Chem. 2013, 13, 871– 891, DOI: 10.2174/1568026611313080002[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpslKhtL8%253D&md5=e860a056db4a4ce8278fd4fcf7cb6efaFluorine-18 labeled amino acids for oncologic imaging with positron emission tomographyHuang, Chaofeng; McConathy, JonathanCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2013), 13 (8), 871-891CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. 18F-labeled amino acids are an important class of imaging agents for positron emission tomog. (PET) that target the increased rates of amino acid transport by many tumor cells. This class of tracers is structurally diverse, and the biol. and imaging properties of a given 18F-labeled amino acid depends largely upon its mechanism of transport. The system L amino acid transport system has been a major focus of tracer development in this field, but more recently 18F-labeled amino acids have been developed for other transporters including system A, glutamine, glutamate and cationic amino acid transport systems. Radiolabeled amino acids are best established for brain tumor imaging, but there are emerging applications in other types of cancer such as neuroendocrine tumors and prostate cancer. This review provides an overview of 18F-labeled amino acids for oncol. imaging in terms of design considerations, radiosynthetic methods, and key clin. applications.
- 124del Amo, E. M.; Urtti, A.; Yliperttula, M. Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2. Eur. J. Pharm. Sci. 2008, 35, 161– 174, DOI: 10.1016/j.ejps.2008.06.015[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVyltrzP&md5=31f6073e1bc3ff74b78773373ba6a9e9Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2del Amo, Eva M.; Urtti, Arto; Yliperttula, MarjoEuropean Journal of Pharmaceutical Sciences (2008), 35 (3), 161-174CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)A review. LAT1 and LAT2 are heterodimeric large amino acid transporters that are expressed in various tissues, including the intestinal wall, blood-brain barrier, and kidney. These transporters consist of membrane spanning light chain and heavy chain, and they act as 1:1 exchangers in concert with other amino acid transporters. Only a few drugs (less than 10) are substrates of LAT1 and LAT2, including -DOPA, alpha-methyldopa, melphalan, and gabapentin. The mechanisms and substrates have been mostly elucidated using mammalian cells and Xenopus oocytes. The in vivo relevance of LAT1 and LAT2 in pharmacokinetics is obscure, because contradictory findings have been reported. It is difficult to make quant. pharmacokinetic conclusions about LAT1 and LAT2. This is due to the possible involvement of other transporters (including cross-linked heterodimers of light chain with different heavy chains, other overlapping transporters, for example TAT1), competing endogenous amino acids, and satn. phenomena. This review presents the current functional knowledge on LAT1 and LAT2 with emphasis on their potential involvement in pharmacokinetics.
- 125Castagna, M.; Shayakul, C.; Trotti, D.; Sacchi, V. F.; Harvey, W. R.; Hediger, M. A. Molecular characteristics of mammalian and insect amino acid transporters: Implications for amino acid homeostasis. J. Exp. Biol. 1997, 200, 269– 286[PubMed], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhslOnsLg%253D&md5=9590e8f83b9875d858bc0cc4c1064e47Molecular characteristics of mammalian and insect amino acid transporters: implications for amino acid homeostasisCastagna, Michela; Shayakul, Chairat; Trotti, Davide; Sacchi, V. Franca; Harvey, William R.; Hediger, Matthias A.Journal of Experimental Biology (1997), 200 (2), 269-286CODEN: JEBIAM; ISSN:0022-0949. (Company of Biologists)A review, with 51 refs. In mammalian cells, the uptake of amino acids is mediated by specialized, energy-dependent and passive transporters with overlapping substrate specificities. Most energy-dependent transporters are coupled either to the cotransport of Na+ or Cl- or to the countertransport of K+. Passive transporters are either facilitated transporters or channels. As a prelude to the mol. characterization of the different classes of transporters, we have isolated transporter cDNAs by expression-cloning with Xenopus laevis oocytes and we have characterized the cloned transporters functionally by uptake studies into oocytes using radiolabeled substrates and by electrophysiol. to det. substrate-evoked currents. Mammalian transporters investigated include the dibasic and neutral amino acid transport protein D2/NBAT (system b0+) and the Na+- and K+-dependent neuronal and epithelial high-affinity glutamate transporter EAAC1 (system X-AG). A detailed characterization of these proteins has provided new information on transport characteristics and mechanisms for coupling to different inorg. ions. This work has furthermore advanced our understanding of the roles these transporters play in amino acid homeostasis and in various pathologies. For example, in the central nervous system, glutamate transporters are critically important in maintaining the extracellular glutamate concn. below neurotoxic levels, and defects of the human D2 gene have been shown to account for the formation of kidney stones in patients with cystinuria. Using similar approaches, we are investigating the mol. characteristics of K+-coupled amino acid transporters in the larval lepidopteran insect midgut. In the larval midgut, K+ is actively secreted into the lumen through the concerted action of an apical H+ V-ATPase and an apical K+/2H+ antiporter, thereby providing the driving force for absorption of amino acids. In vivo, the uptake occurs at extremely high pH (pH 10) and is driven by a large p.d. (approx. -200mV). Studies with brush-border membrane vesicles have shown that there are several transport systems in the larval intestine with distinct amino acid and cation specificities. In addn. to K+, Na+ can also be coupled to amino acid uptake at lower pH, but the Na+/K+ ratio of the hemolymph is so low that K+ is probably the major coupling ion in vivo. The neutral amino acid transport system of larval midgut has been studied most extensively. Apart from its cation selectivity, it appears to be related to the amino acid transport system B previously characterized in vertebrate epithelial cells. Both systems have a broad substrate range which excludes 2-(methylamino)-isobutyric acid, an amino acid analog accepted by the mammalian Na+-coupled system A. To gain insights into the K+-coupling mechanism and into amino acid and K+ homeostasis in insects, current studies are designed to delineate the mol. characteristics of these insect transporters. Recent data showed that injection of mRNA prepd. from the midgut of Manduca sexta into Xenopus laevis oocytes induced a 1.5- to 2.5-fold stimulation of the Na+-dependent uptake of both leucine and phenylalanine (0.2 mmoll-1, pH8). The mol. cloning of these transporters is now in progress. Knowledge of their unique mol. properties could be exploited in the future to control disease vectors and insect pests.
- 126Yanagida, O.; Kanai, Y.; Chairoungdua, A.; Kim, D. K.; Segawa, H.; Nii, T.; Cha, S. H.; Matsuo, H.; Fukushima, J.; Fukasawa, Y.; Tani, Y.; Taketani, Y.; Uchino, H.; Kim, J. Y.; Inatomi, J.; Okayasu, I.; Miyamoto, K.; Takeda, E.; Goya, T.; Endou, H. Human L-type amino acid transporter 1 (LAT1): Characterization of function and expression in tumor cell lines. Biochim. Biophys. Acta, Biomembr. 2001, 1514, 291– 302, DOI: 10.1016/S0005-2736(01)00384-4[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXms1Olsb4%253D&md5=4a4e415390d20b4d1194cc04c103f04eHuman L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell linesYanagida, O.; Kanai, Y.; Chairoungdua, A.; Kim, D. K.; Segawa, H.; Nii, T.; Cha, S. H.; Matsuo, H.; Fukushima, J.-i.; Fukasawa, Y.; Tani, Y.; Taketani, Y.; Uchino, H.; Kim, J. Y.; Inatomi, J.; Okayasu, I.; Miyamoto, K.-i.; Takeda, E.; Goya, T.; Endou, H.Biochimica et Biophysica Acta, Biomembranes (2001), 1514 (2), 291-302CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)System L is a major nutrient transport system responsible for the transport of large neutral amino acids including several essential amino acids. We previously identified a transporter (L-type amino acid transporter 1: LAT1) subserving system L in C6 rat glioma cells and demonstrated that LAT1 requires 4F2 heavy chain (4F2hc) for its functional expression. Since its oncofetal expression was suggested in the rat liver, it has been proposed that LAT1 plays a crit. role in cell growth and proliferation. In the present study, we have examd. the function of human LAT1 (hLAT1) and its expression in human tissues and tumor cell lines. When expressed in Xenopus oocytes with human 4F2hc (h4F2hc), hLAT1 transports large neutral amino acids with high affinity (Km=∼15-∼50 μM) and L-glutamine and L-asparagine with low affinity (Km=∼1.5-∼2 mM). HLAT1 also transports D-amino acids such as D-leucine and D-phenylalanine. In addn., we show that hLAT1 accepts an amino acid-related anti-cancer agent melphalan. When loaded intracellularly, L-leucine and L-glutamine but not L-alanine are effluxed by extracellular substrates, confirming that hLAT1 mediates an amino acid exchange. HLAT1 mRNA is highly expressed in the human fetal liver, bone marrow, placenta, testis and brain. We have found that, while all the tumor cell lines examd. express hLAT1 messages, the expression of h4F2hc is varied particularly in leukemia cell lines. In Western blot anal., hLAT1 and h4F2hc have been confirmed to be linked to each other via a disulfide bond in T24 human bladder carcinoma cells. Finally, in in vitro translation, we show that hLAT1 is not a glycosylated protein even though an N-glycosylation site has been predicted in its extracellular loop, consistent with the property of the classical 4F2 light chain. The properties of the hLAT1/h4F2hc complex would support the roles of this transporter in providing cells with essential amino acids for cell growth and cellular responses, and in distributing amino acid-related compds.
- 127Okubo, S.; Zhen, H.-N.; Kawai, N.; Nishiyama, Y.; Haba, R.; Tamiya, T. Correlation of L-methyl-11C-methionine (MET) uptake with l-type amino acid transporter 1 in human gliomas. J. Neuro-Oncol. 2010, 99, 217– 225, DOI: 10.1007/s11060-010-0117-9[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGmtLbO&md5=419b9c620533421ad74e7bac4ea118ccCorrelation of l-methyl-11C-methionine (MET) uptake with l-type amino acid transporter 1 in human gliomasOkubo, Shuichi; Zhen, Hai-Ning; Kawai, Nobuyuki; Nishiyama, Yoshihiro; Haba, Reiji; Tamiya, TakashiJournal of Neuro-Oncology (2010), 99 (2), 217-225CODEN: JNODD2; ISSN:0167-594X. (Springer)L-Type amino acid transporter 1 (LAT1) is a neutral amino acid transport system and is a major route for the transport of large neutral amino acids, including methionine, through the plasma membrane. LAT1 requires the heavy chain of 4F2 cell surface antigen (4F2hc) for its functional expression. Positron emission tomog. (PET) with l-[methyl-11C] methionine (MET) provides information about amino acid metab. in brain tumors. We conducted a clinicopathol. study to elucidate the correlation of LAT1 and 4F2hc expression with MET uptake in patients with newly diagnosed human gliomas. Thirty-three newly diagnosed glioma patients were enrolled in this study. Uptake of MET in the tumor was evaluated with the max. standardized uptake value (SUVmax). Expression of the LAT1, 4F2hc, and CD34, and Ki-67 labeling index of the tumor were analyzed by immunohistochem. staining, and the correlation with the SUVmax in the tumors was examd. Expression of LAT1 and 4F2hc was higher in high-grade gliomas than in low-grade gliomas. The grade of LAT1 immunostaining increased with glioma grade. LAT1 was mainly expressed in the tumor cytoplasm and vascular endothelium and 4F2hc was mainly expressed in the tumor cytoplasm and plasma membrane. Expression of LAT1 but not 4F2hc was significantly correlated with MET SUVmax. Expression of LAT1 in the tumor vascular endothelium is significantly correlated with CD34 pos. microvessel d. In conclusion, MET SUVmax correlates with LAT1 expression in the tumor in newly diagnosed gliomas. MET transport may be increased by an increased no. of microvessels combined with a higher d. or activity of LAT1 in the tumor endothelial cells in high-grade gliomas. Use of MET-PET as a mol. target combined with anti-angiogenesis in glioma therapy should be addressed in future studies.
- 128Youland, R. S.; Kitange, G. J.; Peterson, T. E.; Pafundi, D. H.; Ramiscal, J. A.; Pokorny, J. L.; Giannini, C.; Laack, N. N.; Parney, I. F.; Lowe, V. J.; Brinkmann, D. H.; Sarkaria, J. N. The role of LAT1 in 18F-DOPA uptake in malignant gliomas. J. Neuro-Oncol. 2013, 111, 11– 18, DOI: 10.1007/s11060-012-0986-1[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFSgtLjP&md5=1dba5787353adb01070974b0876ac9f9The role of LAT1 in 18F-DOPA uptake in malignant gliomasYouland, Ryan S.; Kitange, Gaspar J.; Peterson, Timothy E.; Pafundi, Deanna H.; Ramiscal, Judi A.; Pokorny, Jenny L.; Giannini, Caterina; Laack, Nadia N.; Parney, Ian F.; Lowe, Val J.; Brinkmann, Debra H.; Sarkaria, Jann N.Journal of Neuro-Oncology (2013), 111 (1), 11-18CODEN: JNODD2; ISSN:0167-594X. (Springer)Positron emission tomog. (PET) imaging with the amino acid tracer 6-18F-fluoro-l-3,4-dihydroxy-phenylalanine (18F-DOPA) may provide better spatial and functional information in human gliomas than CT or MRI alone. The l-type amino acid transporter 1 (LAT1) is responsible for membrane transport of large neutral amino acids in normal cells. This study assessed the relationship between LAT1 expression and 18F-DOPA uptake in human astrocytomas. Endogenous LAT1 expression was measured in established glioblastoma (GBM) cell lines and primary GBM xenografts using Western blotting and quant. reverse transcription polymerase chain reaction (qRT-PCR). Uptake of 18F-DOPA was approximated in vitro using 3H-l-DOPA as an analog. Uptake of 3H-l-DOPA was assessed in cells expressing LAT1 shRNA or LAT1 siRNA and compared to non-targeted (NT) control shRNA or siRNA sequences, resp. To demonstrate the clin. relevance of these findings, LAT1 immunofluorescence staining was compared with corresponding regions of 18F-DOPA PET uptake in patients with newly diagnosed astrocytomas. LAT1 mRNA and protein expression varies in GBM, and the extent of 3H-l-DOPA uptake was pos. correlated with endogenous LAT1 expression. Stable shRNA-mediated LAT1 knockdown in T98 and GBM28 reduced 3H-l-DOPA uptake relative to NT shRNA by 57 (P < 0.0001) and 52 % (P < 0.001), resp. Transient siRNA-mediated LAT1 knockdown in T98 reduced 3H-l-DOPA uptake relative to NT siRNA up to 68 % (P < 0.01). In clin. samples, LAT1 expression pos. correlated with 18F-DOPA PET uptake (P = 0.04). Expression of LAT1 is strongly assocd. with 3H-l-DOPA uptake in vitro and 18F-DOPA uptake in patient biopsy samples. These results define LAT1 as a key determinant of 18F-DOPA accumulation in GBM.
- 129Papin-Michault, C.; Bonnetaud, C.; Dufour, M.; Almairac, F.; Coutts, M.; Patouraux, S.; Virolle, T.; Darcourt, J.; Burel-Vandenbos, F. Study of LAT1 expression in brain metastases: Towards a better understanding of the results of positron emission tomography using amino acid tracers. PLoS One 2016, 11, e0157139 DOI: 10.1371/journal.pone.0157139[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslOnsL%252FO&md5=78ac27b61eabe4216a6b0a1eed0a74c3Study of LAT1 expression in brain metastases: towards a better understanding of the results of positron emission tomography using amino acid tracersPapin-Michault, Caroline; Bonnetaud, Christelle; Dufour, Maxime; Almairac, Fabien; Coutts, Mickael; Patouraux, Stephanie; Virolle, Thierry; Darcourt, Jacques; Burel-Vandenbos, FannyPLoS One (2016), 11 (6), e0157139/1-e0157139/12CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Positron emission tomog. using radiolabeled amino acid (PET-AA) appears to be promising in distinguishing between recurrent tumor and radionecrosis in the follow-up of brain metastasis (BM). The amino acid transporter LAT1 and its cofactor CD98, which are involved in AA uptake, have never been investigated in BM. The aim of our study was to det. and compare the expression of LAT1 and CD98 in BM and in non-tumoral brain tissue (NT). The expression of LAT1 and CD98 were studied by immunohistochem. in 67 BM, including 18 BM recurrences after radiotherapy, in 53 NT, and in 13 cases of patients with previously irradiated brain tumor and investigated by [18F] FDOPA-PET. LAT1 and CD98 expression were detected in 98.5%and 59.7%of BM resp. and were significantly assocd. with BM tissue as compared to NT (p<0.001). LAT1 expression in recurrent BM was significantly increased as compared to newly occurring BM. Ten cases investigated by [18F] FDOPA-PET corresponding to recurrent BM displayed significant [18F] FDOPA uptake and LAT1 overexpression whereas three cases corresponding to radionecrosis showed no or low uptake and LAT1 expression. LAT1 expression level and [18F] FDOPA uptake were significantly correlated. In conclusion, we hypothesized that BM may overexpress the AA transporter LAT1.We have shown that LAT1 overexpression was common in BM and was specific for BM as compared to healthy brain. These results could explain the specific BM uptake on PET-AA.
- 130Verrey, F. System L: Heteromeric exchangers of large, neutral amino acids involved in directional transport. Pfluegers Arch. 2003, 445, 529– 533, DOI: 10.1007/s00424-002-0973-z[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjt1Ggu7w%253D&md5=cb3de53aafde4ca0d2a6750f784ff827System L: Heteromeric exchangers of large, neutral amino acids involved in directional transportVerrey, FrancoisPfluegers Archiv (2003), 445 (5), 529-533CODEN: PFLABK; ISSN:0031-6768. (Springer-Verlag)A review. The plasma membrane transport system L is in many cells the only (efficient) pathway for the import of large branched and arom. neutral amino acids. The corresponding transporters are hetero(di)mers composed of a catalytic subunit, LAT1 or LAT2 (light chain glycoprotein-assocd. amino acid transporter), assocd. covalently with the glycoprotein 4F2hc/CD98 (heavy chain). The tissue distribution of LAT1 suggests that it is involved mainly in transporting amino acids into growing cells and across some endothelial/epithelial secretory barriers, whereas the localization of LAT2 indicates that it is mainly involved in the basolateral efflux step of transepithelial (re)absorptive amino acid transport. However, system L transporters are obligatory amino acid exchangers with 1:1 stoichiometry, with similar (but not identical) intra- and extracellular substrate selectivities and with highly asym. apparent affinities (low affinity inside). Therefore, net directional transport of large, neutral amino acids by system L depends on the parallel expression of a unidirectional transporter with overlapping selectivity (for instance systems A or N) that provides/recycles amino acids that drive system L exchange function. By mediating the regulated flux of these exchange substrates, unidirectional transporters control the activity of system L.
- 131Makrides, V.; Bauer, R.; Weber, W.; Wester, H.-J.; Fischer, S.; Hinz, R.; Huggel, K.; Opfermann, T.; Herzau, M.; Ganapathy, V.; Verrey, F.; Brust, P. Preferred transport of O-(2-[18F]fluoroethyl)-D-tyrosine (D-FET) into the porcine brain. Brain Res. 2007, 1147, 25– 33, DOI: 10.1016/j.brainres.2007.02.008[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksVOqtL8%253D&md5=cf68e120baf941dc0aef1399d99f8108Preferred transport of O-(2-[18F]fluoroethyl)-D-tyrosine (D-FET) into the porcine brainMakrides, Victoria; Bauer, Reinhard; Weber, Wolfgang; Wester, Hans-Juergen; Fischer, Steffen; Hinz, Rainer; Huggel, Katja; Opfermann, Thomas; Herzau, Michael; Ganapathy, Vadivel; Verrey, Francois; Brust, PeterBrain Research (2007), 1147 (), 25-33CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)Amino acids are valuable tracers for brain tumor imaging with positron emission tomog. (PET). In this study the transport of O-(2-[18F]fluoroethyl)-D-tyrosine (D-FET) across the blood-brain barrier (BBB) was studied with PET in anesthetized piglets and patients after subtotal resection of brain tumors and compared with O-(2-[18F]fluoroethyl)-L-tyrosine (L-FET) and 3-O-methyl-6-[18F]fluoro-D-DOPA (L-OMFD). In piglets, compartmental modeling of PET data was used to calc. the rate consts. for the blood-brain (K1) and the brain-blood (k2) transfer of D-FET, L-FET and L-OMFD. In patients standardized uptake values (SUVs) were calcd. in brain cortex and lesions. Addnl., affinity detns. on various amino acid transporters (LAT1, LAT2, PAT1, XPCT) were performed in vitro using unlabeled D-FET, L-FET and L-OMFD. The initial brain uptake of D-FET in piglets was more than two-fold higher than that of L-FET, whereas the initial brain uptake of D-FET in patients was similar to that of L-FET. Calcn. of K1 and k2 from the brain uptake curves and the plasma input data in piglets revealed about 4- and 2-fold higher values for D-FET compared to L-FET and L-OMFD, resp. The distribution vol. of D-FET in the piglet brain was slightly higher than that of L-FET as it was also found for most other organs. In brain tumor patients, initial D-FET uptake in the brain was similar to that of L-FET but showed faster tracer washout. L-FET uptake remained rather const. and provided a better delineation of residual tumor than D-FET. In conclusion, our data indicate considerable differences of stereoselective amino acid transport at the BBB in different species. Therefore, the results from animal expts. concerning BBB amino acid transport may not be transferable to humans.
- 132Sun, A.; Liu, X.; Tang, G. Carbon-11 and fluorine-18 labeled amino acid tracers for positron emission tomography imaging of tumors. Front. Chem. 2018, 5, 124, DOI: 10.3389/fchem.2017.00124
- 133Baldessarini, R. J.; Kopin, I. J. S-adenosylmethionine in brain and other tissues. J. Neurochem. 1966, 13, 769– 777, DOI: 10.1111/j.1471-4159.1966.tb09884.x[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28Xks1Oksr0%253D&md5=2e796ae995785216b877230fe3fd81e7S-Adenosylmethionine in brain and other tissuesBaldessarini, Ross J.; Kopin, Irwin J.Journal of Neurochemistry (1966), 13 (8), 769-77CODEN: JONRA9; ISSN:0022-3042.A sensitive and specific isotope diln. method was described for assay of an active Me donor, S-adenosylmethionine (I). Most of the mammalian tissues, including brain, showed measurable amts. of I with the highest levels noted in liver, adrenal, and pineal tissues. The level of I in brain and liver, detd. during various developmental stages of the rats, showed max. activity in the newborn which gradually fell reaching a steady state in the adult animal. The rate of turnover and the level of I in brain was lower than in liver. Since I administered into blood was recovered poorly in brain, it was suggested that I seen in brain might be synthesized locally from methionine entering into the central nervous system.
- 134Veronese, M.; Schmidt, K. C.; Smith, C. B.; Bertoldo, A. Use of spectral analysis with iterative filter for voxelwise determination of regional rates of cerebral protein synthesis with L -[1-11C]leucine PET. J. Cereb. Blood Flow Metab. 2012, 32, 1073– 1085, DOI: 10.1038/jcbfm.2012.27[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvFemt7Y%253D&md5=c01ddf0757e41e95fb8b721695024ae7Use of spectral analysis with iterative filter for voxelwise determination of regional rates of cerebral protein synthesis with L-[1-11C]leucine PETVeronese, Mattia; Schmidt, Kathleen C.; Smith, Carolyn Beebe; Bertoldo, AlessandraJournal of Cerebral Blood Flow & Metabolism (2012), 32 (6), 1073-1085CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)A spectral anal. approach was used to est. kinetic parameters of the L-[1-11C]leucine positron emission tomog. (PET) method and regional rates of cerebral protein synthesis (rCPS) on a voxel-by-voxel basis. Spectral anal. applies to both heterogeneous and homogeneous tissues; it does not require prior assumptions concerning no. of tissue compartments. Parameters estd. with spectral anal. can be strongly affected by noise, but numerical filters improve estn. performance. Spectral anal. with iterative filter (SAIF) was originally developed to improve estn. of leucine kinetic parameters and rCPS in region-of-interest (ROI) data analyses. In the present study, we optimized SAIF for application at the voxel level. In measured L-[1-11C]leucine PET data, voxel-level SAIF parameter ests. averaged over all voxels within a ROI (mean voxel-SAIF) generally agreed well with corresponding ests. derived by applying the originally developed SAIF to ROI time-activity curves (ROI-SAIF). Region-of-interest-SAIF and mean voxel-SAIF ests. of rCPS were highly correlated. Simulations showed that mean voxel-SAIF rCPS ests. were less biased and less variable than ROI-SAIF ests. in the whole brain and cortex; biases were similar in white matter. We conclude that estn. of rCPS with SAIF is improved when the method is applied at voxel level than in ROI anal. Journal of Cerebral Blood Flow & Metab. (2012) 32, 1073-1085; doi:10.1038/jcbfm.2012.27; published online 7 March 2012.
- 135Ishiwata, K.; Vaalburg, W.; Elsinga, P. H.; Paans, A. M.; Woldring, M. G. Comparison of L-[1–11C]methionine and L-methyl-[11C]methionine for measuring in vivo protein synthesis rates with PET. J. Nucl. Med. 1988, 29, 1419– 1427[PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1czgtVaisw%253D%253D&md5=a5fe80f8123662c90cb212d270f17dccComparison of L-[1-11C]methionine and L-methyl-[11C]methionine for measuring in vivo protein synthesis rates with PETIshiwata K; Vaalburg W; Elsinga P H; Paans A M; Woldring M GJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1988), 29 (8), 1419-27 ISSN:0161-5505.To evaluate the feasibility of using either L-[1-11C]-methionine or L-[methyl-11C]methionine for measuring protein synthesis rates by positron emission tomography (PET) in normal and neoplastic tissues, distribution and metabolic studies with 14C- and 11C-labeled methionines were carried out in rats bearing Walker 256 carcinosarcoma. The tissue distributions of the two 14C-labeled methionines were similar except for liver tissue. Similar distribution patterns were observed in vivo by PET using 11C-labeled methionines. The highest 14C incorporation rate into the protein-bound fraction was found in the liver followed by tumor, brain, and pancreas. The incorporation rates in liver and pancreas were different for the two methionines. By chloroform-methanol fractionation of these four tissues, in liver significantly different amounts of 14C were observed in macromolecules. Also in brain tissue slight differences were found. By HPLC analyses of the protein-free fractions of plasma, tumor, and brain tissue at 60 min after injection, for both methionines several 14C-labeled metabolites in different amounts, were detected. About half of the 14C-labeled material in the protein-free fraction was found to be methionine. In these three tissues the amount of nonprotein metabolites and [14C]bicarbonate amount ranged from 10% to 17% and 12% to 15% for L-[1-14C]methionine and L-[methyl-14C]methionine, respectively. From these results it can be concluded that the minor metabolic pathways have to be investigated in order to quantitatively model the protein synthesis by PET.
- 136Lebarre, J.; Crouzel, C.; Donie, P. Preliminary results on the biosynthesis of [11C]phenylalanine using a photosynthetic bacterium. Acta Radiol. Suppl. 1991, 376, 109[PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK383hsVWmtg%253D%253D&md5=d1a825f8674412693fcf6d65f0195bddPreliminary results on the biosynthesis of [11C]phenylalanine using a photosynthetic bacteriumLebarre J; Crouzel C; Donie PActa radiologica. Supplementum (1991), 376 (), 109 ISSN:0365-5954.There is no expanded citation for this reference.
- 137de Boer, J. R.; Pruim, J.; van der Laan, B. F. A. M.; Que, T. H.; Willemsen, A. T. M.; Albers, F. W. J.; Vaalburg, W. L-1-11C-tyrosine PET in patients with laryngeal carcinomas: Comparison of standardized uptake value and protein synthesis rate. J. Nucl. Med. 2003, 44, 341– 346[PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislKntb0%253D&md5=486cda911ea8eaa525f5418177584a19L-1-11C-tyrosine PET in patients with laryngeal carcinomas: comparison of standardized uptake value and protein synthesis ratede Boer, Jurjan R.; Pruim, Jan; van der Laan, Bernard F. A. M.; Que, Tjin H.; Willemsen, Antoon T. M.; Albers, Frans W. J.; Vaalburg, WillemJournal of Nuclear Medicine (2003), 44 (3), 341-346CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)PET with L-1-11C-tyrosine (TYR) can measure and quantify increased protein synthesis in tumor tissue in vivo. For quantification of the protein synthesis rate (PSR), arterial cannulation with repeated blood sampling to obtain the plasma input function and a dynamic TYR PET study to calc. a time-activity curve are necessary. In most PET studies the standardized uptake value (SUV) method is used to quantify tumor activity. The SUV can be calcd. without repeated arterial blood sampling and prolonged scanning time, as required for detn. of the PSR. The relationship between PSR and SUV is largely unknown and different factors can cause wide variability in the SUV. Therefore, the comparison of the abs. quantification method (PSR) with the SUV method is obligatory to det. the possible use of noninvasive PET in head and neck oncol. Methods: Twenty-four patients with proven squamous cell carcinomas of the larynx (T1-T4) were studied using dynamic TYR PET. The PSRs of tumor and nontumor (background) regions were detd. Four different methods were used to calc. the SUV: uncorrected SUV (SUVBW); and SUVs cor. for body surface area (SUVBSA), for lean body mass (SUVLBM), and for the Quetelet index (SUVQI). Correlations between PSR values and SUVs were calcd. Results: The PSR of all tumors was significantly higher (P < 0.001) than the PSR of nontumor tissue. The correlations of SUVBW, SUVBSA, SUVLBM, and SUVQI with the quant. values of the PSR were high (r = 0.84-0.90). The best correlation was obsd. with the SUV based on the LBM (SUVLBM). Conclusion: High correlation between the quant. values (PSR) and the SUVs offers the possibility to use noninvasive TYR PET for detection and reliable quantification of primary head and neck tumors.
- 138Herholz, K.; Holzer, T.; Bauer, B.; Schroder, R.; Voges, J.; Ernestus, R. I.; Mendoza, G.; Weber-Luxenburger, G.; Lottgen, J.; Thiel, A.; Wienhard, K.; Heiss, W. D. 11C-methionine PET for differential diagnosis of low-grade gliomas. Neurology 1998, 50, 1316– 1322, DOI: 10.1212/WNL.50.5.1316[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1c3lsFCiuw%253D%253D&md5=94195d9cfab6935676284088ca0b2ed711C-methionine PET for differential diagnosis of low-grade gliomasHerholz K; Holzer T; Bauer B; Schroder R; Voges J; Ernestus R I; Mendoza G; Weber-Luxenburger G; Lottgen J; Thiel A; Wienhard K; Heiss W DNeurology (1998), 50 (5), 1316-22 ISSN:0028-3878.Management of low-grade gliomas continues to be a challenging task, because CT and MRI do not always differentiate from nontumoral lesions. Furthermore, tumor extent and aggressiveness often remain unclear because of a lack of contrast enhancement. Previous studies indicated that large neutral amino acid tracers accumulate in most brain tumors, including low-grade gliomas, probably because of changes of endothelial and blood-brain barrier function. We describe 11C-methionine uptake measured with PET in a series of 196 consecutive patients, most of whom were studied because of suspected low-grade gliomas. Uptake in the most active lesion area, relative to contralateral side, was significantly different among high-grade gliomas, low-grade gliomas, and chronic or subacute nontumoral lesions, and this difference was independent from contrast enhancement in CT or MRI. Corticosteroids had no significant effect on methionine uptake in low-grade gliomas but reduced uptake moderately in high-grade gliomas. Differentiation between gliomas and nontumoral lesions by a simple threshold was correct in 79%. Recurrent or residual tumors had a higher uptake than primary gliomas. In conclusion, the high sensitivity of 11C-methionine uptake for functional endothelial or blood-brain barrier changes suggests that this tracer is particularly useful for evaluation and follow-up of low-grade gliomas.
- 139Becherer, A.; Karanikas, G.; Szabo, M.; Zettinig, G.; Asenbaum, S.; Marosi, C.; Henk, C.; Wunderbaldinger, P.; Czech, T.; Wadsak, W.; Kletter, K. Brain tumour imaging with PET: A comparison between [18F]fluorodopa and [11C]methionine. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 1561– 1567, DOI: 10.1007/s00259-003-1259-1[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXosVCqtLk%253D&md5=039f1f3fc46c73281b7122386a574388Brain tumour imaging with PET: a comparison between [18F]fluorodopa and [11C]methionineBecherer, Alexander; Karanikas, Georgios; Szabo, Monica; Zettinig, Georg; Asenbaum, Susanne; Marosi, Christine; Henk, Christine; Wunderbaldinger, Patrick; Czech, Thomas; Wadsak, Wolfgang; Kletter, KurtEuropean Journal of Nuclear Medicine and Molecular Imaging (2003), 30 (11), 1561-1567CODEN: EJNMA6; ISSN:1619-7070. (Springer-Verlag)Imaging of amino acid transport in brain tumors is more sensitive than fluorine-18 2-fluoro-deoxyglucose positron emission tomog. (PET). The most frequently used tracer in this field is carbon-11 methionine (MET), which is unavailable for PET centers without a cyclotron because of its short half-life. The purpose of this study was to evaluate the performance of 3,4-dihydroxy-6-[18F]fluoro-phenylalanine (FDOPA) in this setting, in comparison with MET. Twenty patients with known supratentorial brain lesions were referred for PET scans with FDOPA and MET. The diagnoses were 18 primary brain tumors, one metastasis and one non-neoplastic cerebral lesion. All 20 patients underwent PET with FDOPA (100 MBq, 20 min p.i.), and 19 of them also had PET scans with MET (800 MBq, 20 min p.i.). In all but one patient a histol. diagnosis was available. In 15 subjects, histol. was known from previous surgical interventions; in five of these patients, as well as in four previously untreated patients, histol. was obtained after PET. In one untreated patient, confirmation of PET was possible solely by correlation with MRI; a histol. diagnosis became available 10 mo later. MET and FDOPA images matched in all patients and showed all lesions as hot spots with higher uptake than in the contralateral brain. Standardized uptake value ratios, tumor/contralateral side (mean±SD), were 2.05±0.91 for MET and 2.04±0.53 for FDOPA (NS). The benign lesion, which biopsy revealed to be a focal demyelination, was false pos., showing increased uptake of MET and FDOPA. We conclude that FDOPA is accurate as a surrogate for MET in imaging amino acid transport in malignant cerebral lesions for the purpose of visualization of vital tumor tissue. It combines the good phys. properties of 18F with the pharmacol. properties of MET and might therefore be a valuable PET radiopharmaceutical in brain tumor imaging.
- 140Långström, B.; Antoni, G.; Gullberg, P.; Halldin, C.; Malmborg, P.; Någren, K.; Rimland, A.; Svärd, H. Synthesis of L- and D-[methyl-11C]methionine. J. Nucl. Med. 1987, 28, 1037– 1040[PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s3isFWrtQ%253D%253D&md5=75dfaf0560377e6d536b87489db00a24Synthesis of L- and D-[methyl-11C]methionineLangstrom B; Antoni G; Gullberg P; Halldin C; Malmborg P; Nagren K; Rimland A; Svard HJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1987), 28 (6), 1037-40 ISSN:0161-5505.This report describes the synthesis of L- and D-[methyl-11C]methionine in pure enantiomeric forms. The compounds were prepared routinely approximately 1,000 times with less than 20 failures. Starting with carbon-11 (11C) methyl iodide, a simple one-carbon precursor produced from a one-pot or a two-pot apparatus, L- and D-[methyl-11C]methionine were prepared, respectively, with an optical purity higher than 99% in 40%-90% radiochemical yields. The total time for synthesis, starting from [11C]carbon dioxide, was 12-15 min. The crude product usually had a radiochemical purity greater than 95%. The total time for synthesis, including LC purification, was 20-30 min. The radiochemical purity of the product in each case was greater than 98%.
- 141Okochi, Y.; Nihashi, T.; Fujii, M.; Kato, K.; Okada, Y.; Ando, Y.; Maesawa, S.; Takebayashi, S.; Wakabayashi, T.; Naganawa, S. Clinical use of 11C-methionine and 18F-FDG-PET for germinoma in central nervous system. Ann. Nucl. Med. 2014, 28, 94– 102, DOI: 10.1007/s12149-013-0787-4[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVOnsL3F&md5=2909502bf46e171ce67acdf88c01035dClinical use of 11C-methionine and 18F-FDG-PET for germinoma in central nervous systemOkochi, Yoshiyuki; Nihashi, Takashi; Fujii, Masazumi; Kato, Katsuhiko; Okada, Yumiko; Ando, Yoshio; Maesawa, Satoshi; Takebayashi, Shigenori; Wakabayashi, Toshihiko; Naganawa, ShinjiAnnals of Nuclear Medicine (2014), 28 (2), 94-102CODEN: ANMEEX; ISSN:0914-7187. (Springer Japan)Objective: The purpose of this study was to examine the 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) positron emission tomog. (PET) findings of central nervous system (CNS) germinoma and the diagnostic utility of these findings. Methods: We retrospectively evaluated the cases of 10 patients who were diagnosed with CNS germinoma according to their histopathol. or clin. findings. All the patients underwent pretreatment MET and/or FDG-PET scans, and the resultant images were assessed qual. and quant. In the qual. assessments, we used 3- and 5-grade visual scoring systems for the MET- and FDG-PET images, resp. In the quant. assessments, the maximal standardized uptake value (SUVmax) and the ratio of the SUVmax of the tumor (T) divided by the mean SUV for the normal white or gray matter [T/N (WM), T/N (GM)], was calcd. Results: The mean and SD values of SUVmax, T/N (WM), and T/N (GM) were 1.9 ± 1.4, 2.5 ± 1.3, and 1.7 ± 0.9 on MET-PET and 5.8 ± 2.2, 1.6 ± 0.5, and 0.8 ± 0.2 on FDG-PET, resp. On MET-PET, only one lesion was not detected. On the other hand, on FDG-PET all of the lesions exhibited uptake values that were intermediate between those of the normal white matter and gray matter. Conclusion: In terms of its tumor-contouring ability, MET is a good tracer for diagnosing CNS germinomas; therefore, MET-PET is considered to be useful for planning biopsies or surgery. Although FDG-PET is capable of detecting CNS germinomas, it produced insufficient image contrast in the present study. Further studies are needed before FDG-PET can be used in clin. examns. of CNS germinoma.
- 142Phi, J. H.; Paeng, J. C.; Lee, H. S.; Wang, K. C.; Cho, B. K.; Lee, J. Y.; Park, S. H.; Lee, J.; Lee, D. S.; Kim, S. K. Evaluation of focal cortical dysplasia and mixed neuronal and glial tumors in pediatric epilepsy patients using 18F-FDG and 11C-methionine PET. J. Nucl. Med. 2010, 51, 728– 734, DOI: 10.2967/jnumed.109.070920[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3czgslCltQ%253D%253D&md5=c1c6a8190d71b4bfeefee76109d76d6eEvaluation of focal cortical dysplasia and mixed neuronal and glial tumors in pediatric epilepsy patients using 18F-FDG and 11C-methionine petPhi Ji Hoon; Paeng Jin Chul; Lee Hyo Sang; Wang Kyu-Chang; Cho Byung-Kyu; Lee Ji-Yeoun; Park Sung-Hye; Lee Joongyub; Lee Dong Soo; Kim Seung-KiJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2010), 51 (5), 728-34 ISSN:.UNLABELLED: Focal cortical dysplasia (FCD) and mixed neuronal and glial tumors share many clinical characteristics; therefore, the presurgical differential diagnosis of these diseases using MRI is difficult in some cases. The aim of this study was to determine whether (11)C-methionine PET, compared with (18)F-FDG PET, was useful for the evaluation of these diseases. METHODS: The clinical and imaging data of 30 pediatric lesional epilepsy patients pathologically diagnosed with FCD, dysembryoplastic neuroepithelial tumor (DNT), or ganglioglioma were reviewed. Eleven patients had FCD, 8 patients had a DNT, and 11 patients had a ganglioglioma. (18)F-FDG and (11)C-methinine PET scans were obtained from 25 patients and 15 patients, respectively. Visual grading analysis and quantitative assessment of (18)F-FDG and (11)C-methionine PET, represented as a lesion-to-gray matter ratio (LGR), were performed. RESULTS: In the visual grading analysis, both (18)F-FDG PET and (11)C-methionine PET detected a significant difference among the 3 disease groups (P = 0.033 and P = 0.016, respectively), but discrimination of FCD from mixed neuronal and glial tumors was possible only with (11)C-methionine PET. The mean LGR of (18)F-FDG PET was 0.502 +/- 0.119 for FCD, 0.631 +/- 0.107 for DNTs, and 0.620 +/- 0.196 for gangliogliomas; there was no significant difference in LGR among the groups (P = 0.111). However, the mean LGR of (11)C-methionine PET was 1.078 +/- 0.182 for FCD, 1.564 +/- 0.368 for DNT, and 2.114 +/- 0.723 for gangliogliomas; there was a significant difference in LGR among the groups (P = 0.014). Post hoc analysis revealed that the LGR of FCD was significantly different from that of DNTs and gangliogliomas. The mean LGR value of DNTs fell between those of FCD and gangliogliomas. CONCLUSION: Although (18)F-FDG plays a major role in the preoperative work-up of epilepsy surgery patients, it appears from this study that (18)F-FDG does not contribute to the differential diagnosis and that another tracer such as (11)C-methinine is required. (11)C-methinine PET results correlated well with the pathologic spectrum in pediatric lesional epilepsy patients.
- 143Arita, H.; Kinoshita, M.; Okita, Y.; Hirayama, R.; Watabe, T.; Ishohashi, K.; Kijima, N.; Kagawa, N.; Fujimoto, Y.; Kishima, H.; Shimosegawa, E.; Hatazawa, J.; Hashimoto, N.; Yoshimine, T. Clinical characteristics of meningiomas assessed by 11C-methionine and 18F-fluorodeoxyglucose positron-emission tomography. J. Neuro-Oncol. 2012, 107, 379– 386, DOI: 10.1007/s11060-011-0759-2[Crossref], [PubMed], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC383ovFantQ%253D%253D&md5=49a7f78b3de7666f24a9c63aa725a65dClinical characteristics of meningiomas assessed by 11C-methionine and 18F-fluorodeoxyglucose positron-emission tomographyArita Hideyuki; Kinoshita Manabu; Okita Yoshiko; Hirayama Ryuichi; Watabe Tadashi; Ishohashi Kayako; Kijima Noriyuki; Kagawa Naoki; Fujimoto Yasunori; Kishima Haruhiko; Shimosegawa Eku; Hatazawa Jun; Hashimoto Naoya; Yoshimine ToshikiJournal of neuro-oncology (2012), 107 (2), 379-86 ISSN:.The clinical course of meningioma varies from case to case, despite similar characteristics on magnetic resonance (MR) imaging. Functional imaging including (11)C-methionine and (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) has been widely studied for noninvasive preoperative evaluation of brain tumors. However, few reports have examined correlations between meningiomas and findings on (11)C-methionine and FDG PET. The objective of this study was to clarify the relationship between tumor characteristics and (11)C-methionine and FDG uptake in meningiomas. For 68 meningiomas in 51 cases, (11)C-methionine uptake was evaluated by measuring both mean and maximum tumor/normal (T/N) ratio for the whole area of the tumors. FDG uptake in 44 of those meningiomas was also analyzed. Tumor size was measured volumetrically, and tumor-doubling time was estimated. Histopathological evaluation was performed in 19 surgical cases. Mean and maximum T/N ratios of (11)C-methionine PET were significantly higher in skull-base lesions than in non-skull-base lesions. Correlations of mean and maximum T/N ratio of (11)C-methionine PET with tumor-doubling time, MIB-1 labeling index, microvessel density and World Health Organization grading were not significant. Mean T/N ratio of (11)C-methionine PET correlated significantly with tumor volume according to logarithm regression modeling (P < 0.0001, R = 0.544). However, mean and maximum T/N ratio of FDG-PET correlated with none of the tumor characteristics described above. These results suggest that (11)C-methionine uptake correlates with tumor volume, but not with tumor aggressiveness.
- 144Takao, H.; Momose, T.; Ohtomo, K. Methionine and glucose metabolism of central neurocytoma: A PET study. Clinical Nuclear Medicine. 2004, 29, 838– 839, DOI: 10.1097/00003072-200412000-00023[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2crnt1anug%253D%253D&md5=d4fd2edff6cf55c30e3845aad2cc5f74Methionine and glucose metabolism of central neurocytoma: a PET studyTakao Hidemasa; Momose Toshimitsu; Ohtomo KuniClinical nuclear medicine (2004), 29 (12), 838-9 ISSN:0363-9762.There is no expanded citation for this reference.
- 145Van Laere, K.; Ceyssens, S.; Van Calenbergh, F.; de Groot, T.; Menten, J.; Flamen, P.; Bormans, G.; Mortelmans, L. Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: Sensitivity, inter-observer variability and prognostic value. Eur. J. Nucl. Med. Mol. Imaging 2005, 32, 39– 51, DOI: 10.1007/s00259-004-1564-3[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cnivVymtQ%253D%253D&md5=e9a84a1fea65e6826485163d046a4a70Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: sensitivity, inter-observer variability and prognostic valueVan Laere Koen; Ceyssens Sarah; Van Calenbergh Frank; de Groot Tjibbe; Menten Johan; Flamen Patrick; Bormans Guy; Mortelmans LucEuropean journal of nuclear medicine and molecular imaging (2005), 32 (1), 39-51 ISSN:1619-7070.PURPOSE: 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) PET imaging studies allow the investigation of metabolism and amino acid transport in brain tumours. Their (relative) usefulness and prognostic value in suspected recurrence or progression of primary brain tumours after previous therapy is an issue of debate. The aim of this study was to compare directly both radioligands in this setting. METHODS: Cerebral uptake of FDG and MET was determined sequentially on the same day in 30 patients (21 males, nine females; age 40.4+/-15.6 years), on average 4.0 years (range 0.1-18) after therapy for a primary brain tumour (23 grade II-IV astrocytomas, four oligodendrogliomas and three mixed oligo-astrocytomas). Images were acquired on a Siemens HR+ dedicated PET camera. Two observers scored FDG and MET scans independently. Semi-quantitative indices defined by the tumour (maximum)-to-background ratio were calculated based on manual ROI delineation and by using MET ROIs for FDG after automated co-registration. Patient follow-up was conducted until the last contact with inconspicuous clinical findings (average 41 months, range 12-62 months after PET) [(n=10)] or until death (n=20). RESULTS: Overall median survival was 15.0 months. MET showed pathologically increased uptake in 28/30 scans, and FDG in 17/30. The inter-observer agreement was 100% for MET and 73% for FDG. Using Kaplan-Meier survival analysis, significant differences were found for both FDG (cut-off 0.8, log-rank p=0.007) and MET (cut-off 2.2, log-rank p=0.014). The combination of FDG and MET information resulted in the highest prognostic accuracy (p=0.003), while MET alone was the best prognostic predictor in the subgroup of patients with primary astrocytoma (n=23). CONCLUSION: FDG and MET PET studies provide complementary prognostic information in patients with suspected brain tumour recurrence or progression after primary therapy. MET is considered the single agent of choice in the evaluation of these patients because of its sensitivity and clearer delineation of the suspected recurrence.
- 146Galldiks, N.; Kracht, L. W.; Burghaus, L.; Thomas, A.; Jacobs, A. H.; Heiss, W.; Herholz, K. Use of 11C-methionine PET to monitor the effects of Temozolomide chemotherapy in malignant gliomas. Eur. J. Nucl. Med. Mol. Imaging 2006, 33, 516– 524, DOI: 10.1007/s00259-005-0002-5[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XktFSqsLY%253D&md5=3504479e710ed5046d5c51a461aea10fUse of 11C-methionine PET to monitor the effects of temozolomide chemotherapy in malignant gliomasGalldiks, Norbert; Kracht, Lutz W.; Burghaus, Lothar; Thomas, Anne; Jacobs, Andreas H.; Heiss, Wolf-Dieter; Herholz, KarlEuropean Journal of Nuclear Medicine and Molecular Imaging (2006), 33 (5), 516-524CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: The purpose of this study was to monitor the metabolic effects of temozolomide (TMZ) chemotherapy in malignant gliomas by means of repeated positron emission tomog. (PET) with [11C]methionine (MET). Methods: Fifteen patients with histol. proven malignant glioma were treated by TMZ chemotherapy. MET-PET studies were performed before and after the third cycle of TMZ chemotherapy in all patients, and in 12 patients also after the sixth cycle. Gadolinium-enhanced MRI studies were performed in 12 patients before the first and after the sixth cycle. Clin. status was assessed by the modified Rankin scale. Long-term outcome was assessed by calcg. the time to progression (TTP) in months. Results: Decline in MET uptake during therapy corresponded to a stable clin. status. The median TTP was significantly longer in patients with decline in MET uptake than in those with increasing MET uptake (23 vs 3.5 mo; p=0.01, log rank test). There was no significant correlation between change in MET uptake and change in contrast enhancement during treatment for all patients. Conclusion: The present data demonstrate that clin. stability, which is often achieved under TMZ chemotherapy of malignant glioma, corresponds to a decline in or stability of tumor amino acid metab. Tumor responses can already be demonstrated with MET-PET after three cycles of chemotherapy, and absence of progression at that time indicates a high probability of further stability during the next three cycles. A redn. in MET uptake during TMZ treatment predicts a favorable clin. outcome. Mol. imaging of amino acid uptake by MET-PET offers a new method of measurement of the biol. activity of recurrent glioma.
- 147Hatakeyama, T.; Kawai, N.; Nishiyama, Y.; Yamamoto, Y.; Sasakawa, Y.; Ichikawa, T.; Tamiya, T. 11C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma. Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 2009– 2017, DOI: 10.1007/s00259-008-0847-5[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1artLzK&md5=aaa0b92e8fd9738411adabe8e1c733b711C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed gliomaHatakeyama, Tetsuhiro; Kawai, Nobuyuki; Nishiyama, Yoshihiro; Yamamoto, Yuka; Sasakawa, Yasuhiro; Ichikawa, Tomotsugu; Tamiya, TakashiEuropean Journal of Nuclear Medicine and Molecular Imaging (2008), 35 (11), 2009-2017CODEN: EJNMA6; ISSN:1619-7070. (Springer)The purpose of this prospective study was to clarify the individual and combined role of l-methyl-11C-methionine-positron emission tomog. (MET-PET) and 3'-deoxy-3'-[18F]fluorothymidine (FLT)-PET in tumor detection, noninvasive grading, and assessment of the cellular proliferation rate in newly diagnosed histol. verified gliomas of different grades. Forty-one patients with newly diagnosed gliomas were investigated with MET-PET before surgery. Eighteen patients were also examd. with FLT-PET. MET and FLT uptakes were assessed by standardized uptake value of the tumor showing the max. uptake (SUVmax), and the ratio to uptake in the normal brain parenchyma (T/N ratio). All tumors were graded by the WHO grading system using surgical specimens, and the proliferation activity of the tumors were detd. by measuring the Ki-67 index obtained by immunohistochem. staining. On semiquant. anal., MET exhibited a slightly higher sensitivity (87.8%) in tumor detection than FLT (83.3%), and both tracers were 100% sensitive for malignant gliomas. Low-grade gliomas that were false neg. on MET-PET also were false neg. on FLT-PET. Although the difference of MET SUVmax and T/N ratio between grades II and IV gliomas was statistically significant (P < 0.001), there was a significant overlap of MET uptake in the tumors. The difference of MET SUVmax and T/N ratio between grades II and III gliomas was not statistically significant. Low-grade gliomas with oligodendroglial components had relatively high MET uptake. The difference of FLT SUVmax and T/N ratio between grades III and IV gliomas was statistically significant (P < 0.01). Again, the difference of FLT SUVmax and T/N ratio between grades II and III gliomas was not statistically significant. Grade III gliomas with non-contrast enhancement on MR images had very low FLT uptake. In 18 patients who underwent PET examn. with both tracers, a significant but relatively weak correlation was obsd. between the individual SUVmax of MET and FLT (r = 0.54, P < 0.05) and T/N ratio of MET and FLT (r = 0.56, P < 0.05). Total FLT uptake in the tumor had a higher correlation (r = 0.89, P < 0.001) with Ki-67 proliferation index than MET uptake (r = 0.49, P < 0.01). PET studies using MET and FLT are useful for tumor detection in newly diagnosed gliomas. However, there is no complimentary information in tumor detection with simultaneous measurements of MET- and FLT-PET in low grade gliomas. FLT-PET seems to be superior than MET-PET in noninvasive tumor grading and assessment of proliferation activity in gliomas of different grades.
- 148Ishii, K.; Ogawa, T.; Hatazawa, J.; Kanno, I.; Inugami, A.; Fujita, H.; Shimosegawa, E.; Murakami, M.; Okudera, T.; Vemura, K. High L-methyl-[11C]methionine uptake in brain abscess: A PET study. Journal of Computer Assisted Tomography. 1993, 17, 660– 661, DOI: 10.1097/00004728-199307000-00029[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3szit1GgsQ%253D%253D&md5=d7eaaaface3cf39419358ff5208ea75eHigh L-methyl-[11C]methionine uptake in brain abscess: a PET studyIshii K; Ogawa T; Hatazawa J; Kanno I; Inugami A; Fujita H; Shimosegawa E; Murakami M; Okudera T; Uemura KJournal of computer assisted tomography (1993), 17 (4), 660-1 ISSN:0363-8715.There is no expanded citation for this reference.
- 149Sonoda, Y.; Kumabe, T.; Takahashi, T.; Shirane, R.; Yoshimoto, T. Clinical usefulness of 11C-MET PET and 201Tl SPECT for differentiation of recurrent glioma from radiation necrosis. Neurol. Med. Chir. 1998, 38, 342– 348, DOI: 10.2176/nmc.38.342[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1czlsVansA%253D%253D&md5=a2b880750a3f20d4cffee0717fbf0a7eClinical usefulness of 11C-MET PET and 201T1 SPECT for differentiation of recurrent glioma from radiation necrosisSonoda Y; Kumabe T; Takahashi T; Shirane R; Yoshimoto TNeurologia medico-chirurgica (1998), 38 (6), 342-7; discussion 347-8 ISSN:0470-8105.The clinical usefulness of L-methyl-11C-methionine positron emission tomography (11C-MET PET) and thallium-201 single photon emission computed tomography (201T1 SPECT) for distinguishing glioma recurrence from radiation-induced changes was evaluated. Ten patients with lesions highly suggestive of recurrent glioma on magnetic resonance imaging underwent 11C-MET PET and 201T1 SPECT studies. Two patients were examined twice, so a total of 12 studies were performed. The clinical diagnoses were five recurrent gliomas and seven radiation necrosis. The five recurrent gliomas appeared as increased uptakes on both 11C-MET PET and 201T1 SPECT scans. Four of the seven radiation necrosis lesions also appeared as increased uptakes on the 201T1 SPECT scans. In contrast, only one radiation necrosis appeared as increased uptake on the 11C-MET PET scans. There was no significant difference in 201T1 SPECT indices between radiation necrosis and tumor recurrence, but the ratio of the differential absorption ratio of tumor tissue to that of the homologous contralateral gray matter in PET of recurrent glioma was significantly higher than that of radiation necrosis. 11C-MET PET is superior to 201T1 SPECT for the differentiation of tumor recurrence from radiation necrosis and delineation of the extent of the tumor.
- 150Nakagawa, M.; Kuwabara, Y.; Sasaki, M.; Koga, H.; Chen, T.; Kaneko, K.; Hayashi, K.; Morioka, T.; Masuda, K. 11C-methionine uptake in cerebrovascular disease: A comparison with 18F-FDG PET and 99mTc-HMPAO SPECT. Ann. Nucl. Med. 2002, 16, 207– 211, DOI: 10.1007/BF02996302[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmtlGmt7s%253D&md5=4a2d6fb0b53e44b43055382eca58c2f511C-Methionine uptake in cerebrovascular disease: a comparison with 18F-FDG PET and 99mTc-HMPAO SPECTNakagawa, Makoto; Kuwabara, Yasuo; Sasaki, Masayuki; Koga, Hirofumi; Chen, Tao; Kaneko, Kouichirou; Hayashi, Kazutaka; Morioka, Takato; Masuda, KoujiAnnals of Nuclear Medicine (2002), 16 (3), 207-211CODEN: ANMEEX; ISSN:0914-7187. (Japanese Society of Nuclear Medicine)Objectives: Carbon-11-L-methyl-methionine (11C-methionine) has been reported to be useful for evaluating brain tumors, but several other brain disorders have also shown signs of high methionine uptake. We retrospectively evaluated the significance of 11C-methionine uptake in cerebrovascular diseases, and also compared our results with those for 18F-FDG PET and 99mTc-HMPAO SPECT. Methods: Seven patients, including 3 patients with a cerebral hematoma and 4 patients with a cerebral infarction, were examd. All 7 patients underwent both 11C-methionine PET and 99mTc-HMPAO SPECT, and 6 of them underwent 18F-FDG PET. Results: A high 11C-methionine uptake was obsd. in all 3 patients with cerebral hematoma. Increased 99mTc-HMPAO uptake was obsd. in 2 out of 3 patients, and all 3 patients had decreased 18F-FDG uptake. Of 4 patients with a cerebral infarction, high 11C-methionine uptake was obsd. in 3. Increased 99mTc-HMPAO uptake was also obsd. in one patient, whereas 3 patients had decreased 18F-FDG uptake. Conclusions: We should keep in mind that high 11C-methionine uptake is frequently obsd. in cerebrovascular diseases. CVD should therefore be included in the differential diagnosis when encounting patients with a high 11C-methionine uptake.
- 151Tsuyuguchi, N.; Takami, T.; Sunada, I.; Iwai, Y.; Yamanaka, K.; Tanaka, K.; Nishikawa, M.; Ohata, K.; Torii, K.; Morino, M.; Nishio, A.; Hara, M. Methionine positron emission tomography for differentiation of recurrent brain tumor and radiation necrosis after stereotactic radiosurgery —in malignant glioma. Ann. Nucl. Med. 2004, 18, 291– 296, DOI: 10.1007/BF02984466[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpsVGit7c%253D&md5=f0f0d4bec57e1b2b076c8bdccec36b4aMethionine positron emission tomography for differentiation of recurrent brain tumor and radiation necrosis after stereotactic radiosurgery -in malignant glioma-Tsuyuguchi, Naohiro; Takami, Toshihiro; Sunada, Ichiro; Iwai, Yoshiyasu; Yamanaka, Kazuhiro; Tanaka, Kiyoaki; Nishikawa, Misao; Ohata, Kenji; Torii, Kenji; Morino, Michiharu; Nishio, Akimasa; Hara, MitsuhiroAnnals of Nuclear Medicine (2004), 18 (4), 291-296CODEN: ANMEEX; ISSN:0914-7187. (Japanese Society of Nuclear Medicine)Object: Following stereotactic radiosurgery (SRS), we examd. how to differentiate radiation necrosis from recurrent malignant glioma using positron emission tomog. (PET) with 11C-methionine (Met). Methods: Met-PET scans were obtained from 11 adult cases of recurrent malignant glioma or radiation injury, suspected on the basis of magnetic resonance images (MRI). Patients had previously been treated with SRS after primary treatment. PET images were obtained as a static scan of 10 min performed 20 min after injection of Met. We defined two visual grades (e.g., pos. or neg. Met accumulation). On Met-PET scans, the portion of the tumor with the highest accumulation was selected as the region of interest (ROI), tumor-vs.-normal ratio (TN) was defined as the ratio of av. radioisotope counts per pixel in the tumor (T), divided by av. counts per pixel in normal gray matter (N). The standardized uptake value (SUV) was calcd. over the same tumor ROI. Met-PET scan accuracy was evaluated by correlating findings with subsequent histol. anal. (8 cases) or, in cases without surgery or biopsy, by the subsequent clin. course and MR findings (3 cases). Results: Histol. examns. in 8 cases showed viable glioma cells with necrosis in 6 cases, and necrosis without viable tumor cells in 2 cases. Three other cases were considered to have radiation necrosis because they exhibited stable neurol. symptoms with no sign of massive enlargement of the lesion on follow-up MR after 5 mo. Mean TN was 1.31 in the radiation necrosis group (5 cases) and 1.87 in the tumor recurrence group (6 cases). Mean SUV was 1.81 in the necrosis group and 2.44 in the recurrence group. There were no statistically significant differences between the recurrence and necrosis groups in TN or SUV. Furthermore, we made a 2×2 factorial cross table (accumulation or no accumulation, recurrence or necrosis). From this result, the Met-PET sensitivity, specificity, and accuracy in detecting tumor recurrence were detd. to be 100%, 60%, and 82% resp. In a false pos.-case, glial fibrillary acidic protein (GFAP) immunostaining showed a pos. finding. Conclusion: There were no significant differences between recurrent malignant glioma and radiation necrosis following SRS in Met-PET. However, this study shows Met-PET has a sensitivity and accuracy for differentiating between recurrent glioma and necrosis, and presents important information for developing treatment strategies against post radiation reactions.
- 152Minamimoto, R.; Saginoya, T.; Kondo, C.; Tomura, N.; Ito, K.; Matsuo, Y.; Matsunaga, S.; Shuto, T.; Akabane, A.; Miyata, Y.; Sakai, S.; Kubota, K. Differentiation of brain tumor recurrence from post-radiotherapy necrosis with 11C-methionine PET: Visual assessment versus quantitative assessment. PLoS One 2015, 10, e0132515 DOI: 10.1371/journal.pone.0132515[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVWktrbE&md5=bd49d6e38cf3dadc0488a008cd80a74fDifferentiation of brain tumor recurrence from post-radiotherapy necrosis with 11C-methionine PET: visual assessment versus quantitative assessmentMinamimoto, Ryogo; Saginoya, Toshiyuki; Kondo, Chisato; Tomura, Noriaki; Ito, Kimiteru; Matsuo, Yuka; Matsunaga, Shigeo; Shuto, Takashi; Akabane, Atsuya; Miyata, Yoko; Sakai, Shuji; Kubota, KazuoPLoS One (2015), 10 (7), e0132515/1-e0132515/13CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Purpose The aim of this multi-center study was to assess the diagnostic capability of visual assessment in L-methyl-11C-methionine positron emission tomog. (MET-PET) for differentiating a recurrent brain tumor from radiation-induced necrosis after radiotherapy, and to compare it to the accuracy of quant. anal. Methods A total of 73 brain lesions (glioma: 1, brain metastasis: 42) in 70 patients who underwent MET-PET were included in this study. Visual anal. was performed by comparison of MET uptake in the brain lesion with MET uptake in one of four regions (around the lesion, contralateral frontal lobe, contralateral area, and contralateral cerebellar cortex). The concordance rate and logistic regression anal. were used to evaluate the diagnostic ability of visual assessment. Receiver-operating characteristic curve anal. was used to compare visual assessment with quant. assessment based on the lesion-to-normal (L/N) ratio of MET uptake. Results Interobserver and intraobserver κwere highest at 0.657 and 0.714, resp., when assessing MET uptake in the lesion compared to that in the contralateral cerebellar cortex. Logistic regression anal. showed that assessing MET uptake in the contralateral cerebellar cortex with brain metastasis was significantly related to the final result. The highest area under the receiver-operating characteristic curve (AUC) with visual assessment for brain metastasis was 0.85, showing no statistically significant difference with L/Nmax of the contralateral brain (AUC = 0.89) or with L/Nmean of the contralateral cerebellar cortex (AUC = 0.89), which were the areas that were the highest in the quant. assessment. For evaluation of gliomas, no specific candidate was confirmed among the four areas used in visual assessment, and no significant difference was seen between visual assessment and quant. assessment. Conclusion The visual assessment showed no significant difference from quant. assessment of MET-PET with a relevant cut-off value for the differentiation of recurrent brain tumors from radiation-induced necrosis.
- 153Singhal, T.; Alavi, A.; Kim, C. K. Brain: positron emission tomography tracers beyond [18F]fluorodeoxyglucose. PET Clinics. 2014, 9, 267– 276, DOI: 10.1016/j.cpet.2014.03.009[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252Fks12itA%253D%253D&md5=060f3d56739569f2e5659feb81fd97cdBrain: positron emission tomography tracers beyond [18F]fluorodeoxyglucoseSinghal Tarun; Alavi Abass; Kim Chun KPET clinics (2014), 9 (3), 267-76 ISSN:.Several PET radiopharmaceuticals beyond FDG have been used to study the physiology and pathophysiology in neurosciences. This article provides a broad overview of some of the commonly studied radiopharmaceuticals for PET imaging in selected neurologic conditions, particularly attempting to study their clinical relevance. Future studies on the use of advanced PET imaging in delineating neural pathophysiology, drug development, and altering patient management and outcomes across the disciplines of neurosciences are needed.
- 154Nihashi, T.; Dahabreh, I. J.; Terasawa, T. Diagnostic accuracy of PET for recurrent Glioma Diagnosis: A meta-analysis. AJNR Am. J. Neuroradiol. 2013, 34, 944– 950, DOI: 10.3174/ajnr.A3324[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s7gsleitw%253D%253D&md5=b578d485f684e07c374b298e0bf69e44Diagnostic accuracy of PET for recurrent glioma diagnosis: a meta-analysisNihashi T; Dahabreh I J; Terasawa TAJNR. American journal of neuroradiology (2013), 34 (5), 944-50, S1-11 ISSN:.BACKGROUND AND PURPOSE: Studies have assessed PET by using various tracers to diagnose disease recurrence in patients with previously treated glioma; however, the accuracy of these methods, particularly compared with alternative imaging modalities, remains unclear. We conducted a meta-analysis to quantitatively synthesize the diagnostic accuracy of PET and compare it with alternative imaging modalities. MATERIALS AND METHODS: We searched PubMed and Scopus (until June 2011), bibliographies, and review articles. Two reviewers extracted study characteristics, validity items, and quantitative data on diagnostic accuracy. We performed meta-analysis when ≥5 studies were available. RESULTS: Twenty-six studies were eligible. Studies were heterogeneous in treatment strategies and diagnostic criteria of PET; recurrence was typically suspected by CT or MR imaging. The diagnostic accuracies of (18)F-FDG (n = 16) and (11)C-MET PET (n = 7) were heterogeneous across studies. (18)F-FDG PET had a summary sensitivity of 0.77 (95% CI, 0.66-0.85) and specificity of 0.78 (95% CI, 0.54-0.91) for any glioma histology; (11)C-methionine PET had a summary sensitivity of 0.70 (95% CI, 0.50-0.84) and specificity of 0.93 (95% CI, 0.44-1.0) for high-grade glioma. These estimates were stable in subgroup and sensitivity analyses. Data were limited on (18)F-FET (n = 4), (18)F-FLT (n = 2), and (18)F-boronophenylalanine (n = 1). Few studies performed direct comparisons between different PET tracers or between PET and other imaging modalities. CONCLUSIONS: (18)F-FDG and (11)C-MET PET appear to have moderately good accuracy as add-on tests for diagnosing recurrent glioma suspected by CT or MR imaging. Studies comparing alternative tracers or PET versus other imaging modalities are scarce. Prospective studies performing head-to-head comparisons between alternative imaging modalities are needed.
- 155Salber, D.; Stoffels, G.; Pauleit, D.; Oros-Peusquens, A.-M.; Shah, N. J.; Klauth, P.; Hamacher, K.; Coenen, H. H.; Langen, K.-J. Differential uptake of O-(2–18F-fluoroethyl)-L-tyrosine, L-3H-methionine, and 3H-deoxyglucose in brain abscesses. J. Nucl. Med. 2007, 48, 2056– 2062, DOI: 10.2967/jnumed.107.046615[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvFSmug%253D%253D&md5=f97b2467e7200d0bc04ca01ef707abfaDifferential uptake of O-(2-18F-fluoroethyl)-L-tyrosine, L-3H-methionine, and 3H-deoxyglucose in brain abscessesSalber, Dagmar; Stoffels, Gabriele; Pauleit, Dirk; Oros-Peusquens, Anna-Maria; Shah, Nadim Jon; Klauth, Peter; Hamacher, Kurt; Coenen, Heinz Hubert; Langen, Karl-JosefJournal of Nuclear Medicine (2007), 48 (12), 2056-2062CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)The amino acid O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) has been shown to be a useful tracer for brain tumor imaging. Exptl. studies demonstrated no uptake of 18F-FET in inflammatory cells but increased uptake has been reported in single cases of human brain abscesses. To explore this inconsistency, we investigated the uptake of 18F-FET in comparison with that of L-[methyl-3H]methionine (3H-MET) and D-3H-deoxyglucose (3H-DG) in brain and calf abscesses in rats. Methods: Abscesses were induced in the brain (n = 9) and calf (n = 5) of Fisher CDF rats after inoculation of Staphylococcus aureus. Five days later, 18F-FET and 3H-MET (n = 10) or 18F-FET and 3H-DG (n = 4) were injected i.v. One hour after injection the rats were sacrificed, and the brain or calf muscle was investigated using dual-tracer autoradiog. Lesion-to-background ratios (L/B) and standardized uptake values (SUVs) were calcd. The autoradiograms were compared with histol. and immunostaining for glial fibrillary acidic protein (GFAP), CD68 for macrophages, and CD11b for microglia. Results: 18F-FET uptake in the area of macrophage infiltration and activated microglia at the rim of the brain abscesses was low (L/B, 1.5 ± 0.4). In contrast, high uptake was obsd. for 3H-MET as well as for 3H-DG (L/B, 4.1 ± 1.1 for 3H-MET vs. 3.1 ± 1.5 for 3H-DG; P < 0.01 vs. 18F-FET). Results for calf abscesses were similar. In the vicinity of the brain abscesses, slightly increased uptake was noted for 18F-FET (L/B, 1.8 ± 0.3) and 3H-MET (L/B, 1.8 ± 0.4), whereas 3H-DG distribution was normal (L/B, 1.2 ± 0.2). Anti-GFAP immunofluorescence showed a diffuse astrocytosis in those areas. Conclusion: Our results demonstrate that there is no accumulation of 18F-FET in macrophages and activated microglia in exptl. brain abscesses, whereas 3H-MET and 3H-DG exhibit high uptake in these cells. Thus, the specificity of 18F-FET for gliomas may be superior to that 3H-MET and 3H-DG. Increased 18F-FET uptake in human brain abscesses appears to be related to reactive astrocytosis.
- 156Tóth, G.; Lengyel, Z.; Balkay, L.; Salah, M. A.; Trón, L.; Tóth, C. Detection of prostate cancer with 11C-methionine positron emission tomography. J. Urol. 2005, 173, 66– 69, DOI: 10.1097/01.ju.0000148326.71981.44[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cnhvVCgsA%253D%253D&md5=5aaf093849c0ce8deab8e1f8f9ecb27eDetection of prostate cancer with 11C-methionine positron emission tomographyToth Gyorgy; Lengyel Zsolt; Balkay Laszlo; Salah Morshed A; Tron Lajos; Toth CsabaThe Journal of urology (2005), 173 (1), 66-9; discussion 69 ISSN:0022-5347.PURPOSE: We studied the detection of primary prostate cancer with positron emission tomography (PET) using C-labeled methionine (MET) in patients with increased prostate specific antigen (PSA) levels and repeatedly negative biopsies. MATERIALS AND METHODS: A total of 20 consecutive patients with increased serum PSA and negative repeat biopsies were included in the study. Patient age ranged from 52 to 75 years (average 65). PSA levels ranged from 3.49 to 28.6 ng/ml (average 9.36). Dynamic PET images were obtained from the prostate region using C-labeled MET. Suspicious accumulations of the tracer were anatomically localized using magnetic resonance images and were used as guidance during the next biopsy. RESULTS: PET was positive in 15 (75%) patients, in 7 of whom (46.7%) the next repeat biopsy verified carcinoma. The overall detection rate was 35% (7 of 20) and 46.7% (7 of 15) in the whole group and in the positive PET group, respectively. All 5 of 5 patients with negative MET PET had negative biopsies. CONCLUSIONS: MET PET of the prostate with short dynamic scanning and multicore biopsy is a useful method to ensure a high detection rate of prostate cancer in patients with increased PSA and repeat negative biopsies.
- 157Jana, S.; Blaufox, M. D. Nuclear medicine studies of the prostate, testes, and bladder. Semin. Nucl. Med. 2006, 36, 51– 72, DOI: 10.1053/j.semnuclmed.2005.09.001[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnntVaguw%253D%253D&md5=bc58a76171ac93293e2ecc5ad2edaf90Nuclear medicine studies of the prostate, testes, and bladderJana Suman; Blaufox M DonaldSeminars in nuclear medicine (2006), 36 (1), 51-72 ISSN:0001-2998.During the last decade, there has been a significant advancement in imaging of urologic diseases. Transrectal ultrasound (TRUS), computerized tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) are still experiencing new developments in urology. Despite these many technological advances, the initial diagnostic procedure for a patient with suspected prostate cancer (PC) is multiple site blind prostate biopsies. There is a need for a noninvasive metabolic imaging modality to direct the site of biopsy to decrease the sampling error. MRS seems promising but as it is a costly and more time-consuming test, further studies are needed to evaluate its clinical utility. Currently, PET does not play any role to direct biopsy. Acetate and choline appear to be better tracers than FDG for the detection of a prostate lesion, however, further well-organized studies are needed before any of these agents can be used clinically. Incidental detection of intense focal uptake in the prostate during whole body PET scanning should be evaluated with prostate-specific antigen (PSA) and TRUS-guided biopsy. Although FDG is inferior to other tracers for primary staging, it may be useful in selected patients with suspected high-grade cancer. The role of ProstaScint scan is still controversial for detection of recurrent PC. This study may be helpful for evaluating nodal metastases when PSA is elevated and bone scan is negative. Bone scan remains the study of choice when bone metastases are suspected (PSA>15-20 ng/mL+/-bone pain). Acetate and choline provide better accuracy than FDG in the detection of local soft tissue disease, nodal involvement, and distant metastases. High FDG uptake may be indicative of more aggressive and possibly androgen-independent disease. PET/CT with any of the above PET tracers will most likely be preferred to the PET scan alone due to better localization of a hot lesion in PET/CT. Nuclear medicine studies also have been used to evaluate acute scrotum and testicular neoplasms. Scrotal scintigraphy has lost its popularity to Doppler ultrasound in the evaluation of the acute scrotum. In testicular tumors, FDG-PET appears to be superior to conventional imaging modalities in initial staging, detection of residual/recurrence, and monitoring treatment response. Tumor markers after treatment occasionally are elevated and cannot locate the site of recurrence, FDG-PET can play a very important role in this regard. Nuclear medicine studies also have been used to evaluate diseases of the urinary bladder. Radionuclide cystography is more sensitive and has less than 1/20 the radiation exposure of the conventional contrast enhanced micturating cystourethrogram (MCU). However, the utility of FDG-PET in the evaluation of bladder cancer seems to be limited to the evaluation of distant metastases. 11C-Methionine and choline may be a better option for local and nodal disease due to their negligible excretion in the urine.
- 158Deng, H.; Tang, X.; Wang, H.; Tang, G.; Wen, F.; Shi, X.; Yi, C.; Wu, K.; Meng, Q. S-11C-methyl-L-cysteine: A new amino acid PET tracer for cancer imaging. J. Nucl. Med. 2011, 52, 287– 293, DOI: 10.2967/jnumed.110.081349[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisF2ku7Y%253D&md5=e10679f12a5b5b1756dad6b9d6c655edS-11C-methyl-L-cysteine: a new amino acid PET tracer for cancer imagingDeng, Huaifu; Tang, Xiaolan; Wang, Hongliang; Tang, Ganghua; Wen, Fuhua; Shi, Xinchong; Yi, Chang; Wu, Kening; Meng, QuanfeiJournal of Nuclear Medicine (2011), 52 (2), 287-293CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)S-11C-methyl-L-cysteine (11C-MCYS), an analog of S-11C-methyl-L-methionine (11C-MET), can potentially serve as an amino acid PET tracer for tumor imaging. The aim of this study was to investigate the radiosynthesis and perform a biol. evaluation of 11C-MCYS as a tumor imaging tracer. The results of the first human PET study are reported. Methods: 11C-MCYS was prepd. by 11C-methylation of the precursor L-cysteine with 11CH3I and purifn. on com. C18 cartridges. In vitro competitive inhibition expts. were performed with Hepa1-6 hepatoma cell lines, and biodistribution of 11C-MCYS was detd. in normal mice. The incorporation of 11C-MCYS into tissue proteins was investigated. In vivo 11C-MCYS uptake studies were performed on hepatocellular carcinoma-bearing nude mice and inflammation models and compared with 11C-MET PET and 18F-FDG PET. In a human PET study, a patient with a recurrence of glioma after surgery was examd. with 11C-MCYS PET and 18F-FDG PET. Results: The uncorrected radiochem. yield of 11C-MCYS from 11CH3I was more than 50% with a synthesis time of 2 min, the radiochem. purity of 11C-MCYS was more than 99%, and the enantiomeric purity was more than 90%. In vitro studies showed that 11C-MCYS transport was mediated through transport system L. Biodistribution studies demonstrated high uptake of 11C-MCYS in the liver, stomach wall, and heart and low uptake of 11C-MCYS in the brain. There was higher accumulation of 11C-MCYS in the tumor than in the muscles. The tumor-to-muscle and inflammatory lesion-to-muscle ratios were 7.27 and 1.62, resp., for 11C-MCYS, 5.08 and 3.88, resp., for 18F-FDG, and 4.26 and 2.28, resp., for 11C-MET at 60 min after injection. Almost no 11C-MCYS was incorporated into proteins. For the patient PET study, high uptake of 11C-MCYS with true-pos. results, but low uptake of 18F-FDG with false-neg. results, was found in the recurrent glioma. Conclusion: Automated synthesis of 11C-MCYS is easy to perform. 11C-MCYS is superior to 11C-MET and 18F-FDG in the differentiation of tumor from inflammation and seems to have potential as an oncol. PET tracer for the diagnosis of solid tumors.
- 159Huang, T.; Tang, G.; Wang, H.; Nie, D.; Tang, X.; Liang, X.; Hu, K.; Yi, C.; Yao, B.; Tang, C. Synthesis and preliminary biological evaluation of S-11C-methyl-D-cysteine as a new amino acid PET tracer for cancer imaging. Amino Acids 2015, 47, 719– 727, DOI: 10.1007/s00726-014-1899-4[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFCrurjI&md5=877ce201aac02f6b8ea75d68c36dfea6Synthesis and preliminary biological evaluation of S-11C-methyl-D-cysteine as a new amino acid PET tracer for cancer imagingHuang, Tingting; Tang, Ganghua; Wang, Hongliang; Nie, Dahong; Tang, Xiaolan; Liang, Xiang; Hu, Kongzhen; Yi, Chang; Yao, Baoguo; Tang, CaihuaAmino Acids (2015), 47 (4), 719-727CODEN: AACIE6; ISSN:0939-4451. (Springer-Verlag GmbH)S-11C-methyl-L-cysteine (LMCYS) is an attractive amino acid tracer for clin. tumor positron emission tomog. (PET) imaging. D-Isomers of some radiolabeled amino acids are potential PET tracers for tumor imaging. In this work, S-11C-methyl-D-cysteine (DMCYS), a D-amino acid isomer of S-11C-methyl-cysteine for tumor imaging was developed and evaluated. DMCYS was prepd. by 11C-methylation of the precursor D-cysteine, with an uncorrected radiochem. yield over 50 % from 11CH3I within a total synthesis time from 11CO2 about 12 min. In vitro competitive inhibition studies showed that DMCYS uptake was primarily transported through the Na+-independent system L, and also the Na+-dependent system B0,+ and system ASC, with almost no system A. In vitro incorporation expts. indicated that almost no protein incorporation was found in Hepa 1-6 hepatoma cell lines. Biodistribution studies demonstrated higher uptake of DMCYS in pancreas and liver at 5 min post-injection, relatively lower uptake in brain and muscle, and faster radioactivity clearance from most tissues than those of L-isomer during the entire observation time. In the PET imaging of S180 fibrosarcoma-bearing mice and turpentine-induced inflammatory model mice, 2-18F-fluoro-2-deoxy-D-glucose (FDG) exhibited significantly high accumulation in both tumor and inflammatory lesion with low tumor-to-inflammation ratio of 1.40, and LMCYS showed low tumor-to-inflammation ratio of 1.64 at 60 min post-injection. By contrast, DMCYS showed moderate accumulation in tumor and very low uptake in inflammatory lesion, leading to relatively higher tumor-to-inflammation ratio of 2.25 than 11C-methyl-L-methionine (MET) (1.85) at 60 min post-injection. Also, PET images of orthotopic transplanted glioma models demonstrated that low uptake of DMCYS in normal brain tissue and high uptake in brain glioma tissue were obsd. The results suggest that DMCYS is a little better than the corresponding L-isomers as a potential PET tumor-detecting agent and is superior to MET and FDG in the differentiation of tumor from inflammation.
- 160Sutinen, E.; Jyrkkiö, S.; Alanen, K.; Någren, K.; Minn, H. Uptake of [N-methyl-11C]α-methylaminoisobutyric acid in untreated head and neck cancer studied by PET. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 72– 77, DOI: 10.1007/s00259-002-1010-3[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpsV2iu70%253D&md5=4cb3ba676b42b451c1885cd1719fac6dUptake of [N-methyl-11C]α-methylaminoisobutyric acid in untreated head and neck cancer studied by PETSutinen, Eija; Jyrkkioe, Sirkku; Alanen, Kalle; Nagren, Kjell; Minn, HeikkiEuropean Journal of Nuclear Medicine and Molecular Imaging (2003), 30 (1), 72-77CODEN: EJNMA6; ISSN:1619-7070. (Springer-Verlag)Amino acid transport system A is expressed strongly in neoplastic cells. [N-methyl-11C]α-Methylaminoisobutyric acid (11C-MeAIB) is a recently developed tracer for PET studies on system A amino acid transport. 11C-MeAIB is a metabolically stable amino acid analog which is transported from plasma into the tissue by system A. This study evaluated the kinetics of 11C-MeAIB uptake from plasma into tumor tissue and normal tissues in 13 patients with untreated head and neck cancer. 11C-MeAIB uptake in tumor was compared with histol. grade and proliferative activity. Tracer uptake was quantitated by calcg. the standardized uptake values (SUVs) and the kinetic influx consts. (Ki) using graphical anal. All tumors accumulated 11C-MeAIB and were visualised clearly. In the graphical anal., linear plots were achieved; the mean Ki value of tumor was 0.056±0.026 min-1, and the mean SUV was 6.1±2.7. A close correlation between graphically obtained Ki and semi-quant. SUV in tumors was found (r=0.887, P=0.00005). We could not demonstrate a correlation between the uptake of 11C-MeAIB and the grade of malignancy or the proliferative index, as assessed using Ki-67 immunohistochem. assay. Head and neck cancer can be effectively imaged with 11C-MeAIB PET. 11C-MeAIB showed active and rapid transport into tumor tissue and salivary glands. Further studies on the applicability of 11C-MeAIB PET for radiation treatment planning in the head and neck region and the regulation of system A amino acid transport under different metabolic states are warranted.
- 161Nishii, R.; Higashi, T.; Kagawa, S.; Kishibe, Y.; Takahashi, M.; Yamauchi, H.; Motoyama, H.; Kawakami, K.; Nakaoku, T.; Nohara, J.; Okamura, M.; Watanabe, T.; Nakatani, K.; Nagamachi, S.; Tamura, S.; Kawai, K.; Kobayashi, M. Diagnostic usefulness of an amino acid tracer, α-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB), in the PET diagnosis of chest malignancies. Ann. Nucl. Med. 2013, 27, 808– 821, DOI: 10.1007/s12149-013-0750-4[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVWlu7rL&md5=b4bb81af65105b1ee8814d32518e81f5Diagnostic usefulness of an amino acid tracer, α-[N-methyl-11C|-methylaminoisobutyric acid (11C-MeAIB), in the PET diagnosis of chest malignanciesNishii, Ryuichi; Higashi, Tatsuya; Kagawa, Shinya; Kishibe, Yoshihiko; Takahashi, Masaaki; Yamauchi, Hiroshi; Motoyama, Hideki; Kawakami, Kenzo; Nakaoku, Takashi; Nohara, Jun; Okamura, Misato; Watanabe, Toshiki; Nakatani, Koichi; Nagamachi, Shigeki; Tamura, Shozo; Kawai, Keiichi; Kobayashi, MasatoAnnals of Nuclear Medicine (2013), 27 (9), 808-821CODEN: ANMEEX; ISSN:0914-7187. (Springer Japan)Objectives: Although positron emission tomog. (PET) using [18F]-fluoro-2-deoxy-D-glucose (18F-FDG) is established as one of the first-choice imaging modalities in the diagnosis of chest malignancies, there are several problems to solve in clin. practice, such as false pos. uptake in inflammatory diseases. The aim of this study was to evaluate the clin. usefulness of an amino acid tracer, α-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB), in the diagnosis of chest malignancies, in combination with 18F-FDG. Setting: Fifty-nine cases (57 patients, 66 ± 12 years old) who consulted to our institution for the wish to receive differential diagnosis of chest diseases were included. Purpose of the studies were as follows: differential diagnosis of newly developed lung nodules, n = 22; newly developed mediastinal lesions, n = 20; and both, n = 17 (including lung cancer: n = 19, lymphoma: n = 1, other cancers: n = 2, sarcoidosis: n = 15, non-specific inflammation: n = 18, other inflammatory: n = 4, resp.). Whole-body static PET or PET/CT scan was performed 20 and 50 min after the IV injection of 11C-MeAIB and 18F-FDG, resp. Results: 11C-MeAIB uptake of malignant and benign lesions was statistically different both in pulmonary nodules (p < 0.005) and in mediastinal lesions (p < 0.0005). In visual differential diagnosis, 11C-MeAIB showed higher results (specificity: 73 %, accuracy: 81 %), compared to those in 18F-FDG (60, 73 %, resp.). In cases of sarcoidosis, 11C-MeAIB showed higher specificity (80 %) with lower uptake (1.8 ± 0.7) in contrast to the lower specificity (60 %) with higher uptake of 18F-FDG (7.3 ± 4.5). Conclusions: 11C-MeAIB PET/CT was useful in the differential diagnosis of pulmonary and mediastinal mass lesions found on CT. 11C-MeAIB PET or PET/CT showed higher specificity than that of 18F-FDG PET/CT in differentiating between benign and malignant disease. Our data suggest that the combination of 18F-FDG and 11C-MeAIB may improve the evaluation of chest lesions, when CT and 18F-FDG PET/CT are equivocal.
- 162Washburn, L. C.; Sun, T. T.; Anon, J. B.; Hayes, R. L. Effect of structure on tumor specificity of alicyclic alpha-amino acids. Cancer Res. 1978, 38, 2271– 2273[PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXmtFWhs7o%253D&md5=f1b3a75c68924d8811527eca033b2778Effect of structure on tumor specificity of alicyclic α-amino acidsWashburn, Lee C.; Sun, Tan Tan; Anon, Jack B.; Hayes, Raymond L.Cancer Research (1978), 38 (8), 2271-3CODEN: CNREA8; ISSN:0008-5472.The selective affinity of 1-aminocyclopentanecarboxylic-carboxyl-14C acid (I) for tumor tissue led to the study of the tumor-localizing characteristics of a series of alicyclic α-amino acid analogs of I. The tissue distributions of 1-aminocyclopropanecarboxylic-14C acid, 1-aminocyclobutanecarboxylic-14C acid (II), 1-aminocyclohexanecarboxylic-14C acid, 1-amino-2-methylcyclopentanecarboxylic-14C acid, and 1-amino-3-methylcyclopentanecarboxylic-14C acid were compared with that of I in Buffalo rats bearing Morris 5123C hepatomas. I and II had higher tumor/nontumor concn. ratios than the other 4 amino acids. II generally had higher tumor/nontumor ratios than did I, significantly so for muscle, kidney, and testis, and marginally so for blood. Evidently, II may be a better agent than I for tumor imaging by positron tomog.
- 163Vis, K. D.; Schelstraete, K.; Deman, J.; Vermeulen, F. L.; Sambre, J.; Goethals, P.; Haver, D. V.; Slegers, G.; Vandecasteele, C.; Schryver, A. D. Clinical comparison of 11C-ACPC (aminocyclopentane carboxylic acid) and 13N-ammonia as tumour tracers. Acta Oncol. 1987, 26, 105– 111, DOI: 10.3109/02841868709091749
- 164Öberg, K.; Castellano, D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev. 2011, 30 (S1), 3– 7, DOI: 10.1007/s10555-011-9292-1[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3msVKqtw%253D%253D&md5=3896b1208cae508c31e3263c907aef85Current knowledge on diagnosis and staging of neuroendocrine tumorsOberg Kjell; Castellano DanielCancer metastasis reviews (2011), 30 Suppl 1 (), 3-7 ISSN:.Neuroendocrine tumors (NETs) consist of a heterogeneous group of malignancies with various clinical presentations and growth rates. The incidence has been estimated to 2.5-5 per 100,000 people per year and prevalence of 35 per 100,000. The largest group is the gastroenteropancreatic NETs. Small intestinal NETs are the most common followed by pancreatic NETs in the gastrointestinal tract. A classification system (World Health Organization) was established in year 2000 and recently updated in 2010, taking into consideration the histopathology and tumor biology of the tumors. To further refine the classification a "tumor node metastasis" staging has been suggested by the European Neuroendocrine Tumor Society. The same organization has also proposed a grading system (G1, G2, and G3). The diagnosis of a NET is based on histopathology on tumor specimens, circulating biomarkers as well as imaging. Traditional radiology, such as computerized tomography and magnetic resonance imaging, is still the basis but is complemented with somatostatin receptor scintigraphy and positron emission tomography with specific isotopes such (68)Ga-DOTA-octreotate, F18-dopamine, or C11-5 hydroxytryptamine. Molecular imaging will increase in importance in the near future. There is still an unmet need for more sensitive biomarkers for diagnosis and follow-up.
- 165Toumpanakis, C.; Kim, M. K.; Rinke, A.; Bergestuen, D. S.; Thirlwell, C.; Khan, M. S.; Salazar, R.; Oberg, K. Combination of cross-sectional and molecular imaging studies in the localization of gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology 2014, 99, 63– 74, DOI: 10.1159/000358727[Crossref], [PubMed], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1WqtrfI&md5=a63f62b0b8ccadd1f9cec8bd7429089dCombination of Cross-Sectional and Molecular Imaging Studies in the Localization of Gastroenteropancreatic Neuroendocrine TumorsToumpanakis, Christos; Kim, Michelle K.; Rinke, Anja; Bergestuen, Deidi S.; Thirlwell, Christina; Khan, Mohid S.; Salazar, Ramon; Oberg, KjellNeuroendocrinology (2014), 99 (2), 63-74CODEN: NUNDAJ; ISSN:0028-3835. (S. Karger AG)A review. Mol. imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiol. for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET det. which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available mol. imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clin. scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 (68Ga)-DOTA positron emission tomog. (PET) techniques may replace SRS in the future, not only because of their tech. advantages, but also because they are superior in patients with small-vol. disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 (11C)-5-hydroxy-L-tryptophan (5-HTP) PET and 18F-dihydroxyphenylalanine (18F-DOPA) PET are new mol. imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of 68Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 (18F)-fluorodeoxyglucose (18F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, 18F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, 18F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining mol. imaging techniques (e.g. 18F-FDG PET and 68Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned mol. imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up.
- 166Orlefors, H.; Sundin, A.; Garske, U.; Juhlin, C.; Oberg, K.; Skogseid, B.; Langstrom, B.; Bergstrom, M.; Eriksson, B. Whole-body 11C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: Comparison with somatostatin receptor scintigraphy and computed tomography. J. Clin. Endocrinol. Metab. 2005, 90, 3392– 3400, DOI: 10.1210/jc.2004-1938[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkvFCltrc%253D&md5=284ac4d7911dc287630f4e2864d7b42bWhole-body 11C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: Comparison with somatostatin receptor scintigraphy and computed tomographyOrlefors, H.; Sundin, A.; Garske, U.; Juhlin, C.; Oberg, K.; Skogseid, B.; Langstrom, B.; Bergstrom, M.; Eriksson, B.Journal of Clinical Endocrinology and Metabolism (2005), 90 (6), 3392-3400CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)Neuroendocrine tumors (NETs) can be small and situated almost anywhere throughout the body. Our objective was to investigate whether whole-body (WB) positron emission tomog. (PET) with 11C-5-hydroxytryptophan (5-HTP) can be used as a universal imaging technique for NETs and to compare this technique with established imaging methods. Forty-two consecutive patients with evidence of NET and a detected lesion on any conventional imaging (six bronchial, two foregut, 16 midgut, and two thymic carcinoids; one ectopic Cushing's syndrome; four gastrinomas; one insulinoma; six nonfunctioning endocrine pancreatic tumors; one gastric carcinoid, one paraganglioma; and two endocrine-differentiated pancreatic carcinomas) were studied. The WB-11C-5-HTP-PET examns. were compared with WB-computed tomog. (CT) and somatostatin receptor scintigraphy (SRS). Tumor lesions were imaged with PET in 95% of the patients. In 58% of the patients, PET could detect more lesions than SRS and CT and equal nos. in 34%, whereas in three cases, SRS or CT showed more lesions. In 84% (16 of 19 patients), PET could visualize the primary tumor compared with 47 and 42% for SRS and CT, resp. The surgically removed PET-pos. primary tumor sizes were 6-30 mm. To conclude, this study indicates that WB-11C-5-HTP-PET can be used as a universal imaging method for detection of NETs. This study also shows that WB-11C-HTP-PET is sensitive in imaging small NET lesions, such as primary tumors, and can in a majority of cases image significantly more tumor lesions than SRS and CT.
- 167Eriksson, B.; Orlefors, H.; Oberg, K.; Sundin, A.; Bergström, M.; Långström, B. Developments in PET for the detection of endocrine tumours. Best Pract. Res. Clin. Endocrinol. Metab. 2005, 19, 311– 324, DOI: 10.1016/j.beem.2004.11.001[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M7jtFygug%253D%253D&md5=db0a61fee0d04a8e08ee688fc6454d45Developments in PET for the detection of endocrine tumoursEriksson B; Orlefors H; Oberg K; Sundin A; Bergstrom M; Langstrom BBest practice & research. Clinical endocrinology & metabolism (2005), 19 (2), 311-24 ISSN:1521-690X.Positron emission tomography (PET) supplies a range of labelled compounds to be used for the characterization of tumour biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow-up, and clinical research. (18)F-fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology, reflecting increased expression of glucose transporters in cancerous tissue. This tracer, however, does not show sufficient uptake in well-differentiated tumours such as neuroendocrine tumours. Endocrine tumours have the unique characteristics of taking up and decarboxylating amine precursors. These so-called APUD characteristics offer highly specific targets for PET tracers. Using this approach, radiopharmaceuticals such as [(11)C]-5-hydroxytryptophan and [(11)C]-L-dihydroxyphenylalanine for localization of carcinoid and endocrine pancreatic tumours, 6-[(18)F]-fluorodopamine and [(11)C]-hydroxyephedrine for phaeochromocytomas, and [(11)C]-metomidate for adrenal cortical tumours have been developed. Functional imaging with PET using these compounds is now being employed to complement rather than replace other imaging modalities. Development of new PET radiopharmaceuticals may in the future allow in vivo detection of tumour biological properties, such as malignant potential and responsiveness to treatment.
- 168Bjurling, P.; Watanabe, Y.; Tokushige, M.; Oda, T.; Långström, B. Syntheses of β-11C-labelled L-tryptophan and 5-hydroxy-L-tryptophan using a multi-enzymatic reaction route. J. Chem. Soc., Perkin Trans. 1 1989, 7, 1331– 1334, DOI: 10.1039/P19890001331
- 169Pruim, J.; Willemsen, A. T.; Molenaar, W. M.; van Waarde, A.; Paans, A. M.; Heesters, M. A.; Go, K. G.; Visser, G. M.; Franssen, E. J.; Vaalburg, W. Brain Tumors: L-[1-C-11]tyrosine PET for visualization and quantification of protein synthesis rate. Radiology 1995, 197, 221– 226, DOI: 10.1148/radiology.197.1.7568827[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXptlaksL4%253D&md5=76631465424928518d63ab69d41bfc7aBrain tumors: L-[1-C-11]tyrosine PET for visualization and quantification of protein synthesis ratePruim, Jan; Willemsen, Antoon T. M.; Molenaar, Willemina M.; van Waarde, Aren; Paans, Anne M. J.; Heesters, Martinus A. A. M.; Go, K. Gwan; Visser, Gerben M.; Franssen, Eric J. F.; Vaalburg, WillemRadiology (Oak Brook, Illinois) (1995), 197 (1), 221-6CODEN: RADLAX; ISSN:0033-8419. (Radiological Society of North America)Positron emission tomog. (PET) with the amino acid tracer L-[1-C-11]-tyrosine was evaluated in 27 patients with primary and recurrent brain tumors. Patients underwent either static (n = 14) or dynamic PET (n = 13), with quantification of protein synthesis rate (PSR) and tumor-to-background ratio. Findings were compared with histol. findings. Primary brain tumor was proved in 22 patients histol., as well as metastatic cancer of unknown origin, primary non-Hodgkin lymphoma, meningioma, atypical infarction, and vasculitis in one patient each. At PET, 20 of 22 primary tumors, the metastasis, and non-Hodgkin lymphoma were correctly depicted. A false-pos. finding was obtained with the infarction, and the meningioma and vasculitis were not depicted. The calcd. sensitivity was 92%; specificity, 67%; and accuracy, 89%. There were no statistically significant relationships between histol. findings, PSR, and tumor-to-background ratio. L-[1-C-11]-tyrosine is a valid tracer for diagnosis of brain tumors and allowed quantification of PSR.
- 170Kole, A. C.; Nieweg, O. E.; Pruim, J.; Paans, A. M.; Plukker, J. T.; Hoekstra, H. J.; Schraffordt Koops, H.; Vaalburg, W. Standardized uptake value and quantification of metabolism for breast cancer imaging with FDG and L-[1–11C]tyrosine PET. J. Nucl. Med. 1997, 38, 692– 696[PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2szhsVSrtQ%253D%253D&md5=4eb88a689e5ccf0018ef27d767e98fc0Standardized uptake value and quantification of metabolism for breast cancer imaging with FDG and L-[1-11C]tyrosine PETKole A C; Nieweg O E; Pruim J; Paans A M; Plukker J T; Hoekstra H J; Schraffordt Koops H; Vaalburg WJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1997), 38 (5), 692-6 ISSN:0161-5505.UNLABELLED: The aims of the study were to compare the value of L-[1-11C]tyrosine (TYR) and [IBF]fluoro-2-deoxy-D-glucose (FDG) as tumor tracers in patients with breast cancer, to investigate the correlation between quantitative values and standardized uptake values (SUVs) and to estimate the value of SUVs for the evaluation of therapy. METHODS: Eleven patients with one or more malignant breast lesions and two patients with one or more benign breast tumors were studied with TYR and FDG. Doses of 300 MBq of TYR and 230 MBq of FDG were given intravenously. All PET sessions were performed using a Siemens ECAT 951/31 camera. Of 10 malignant tumors and the 3 benign lesions, glucose consumption and protein synthesis rate were quantified. All lesions were studied using SUVs based on body weight, body surface area and lean body mass, with and without correction for plasma glucose or tyrosine levels. RESULTS: All malignant tumors were visualized with both FDG and TYR, but the visual contrast was better with FDG. Increased uptake of the tracers was seen in patients with fibrocystic tissue and complicated the visual assessment and the outlining of tumor tissue. Uptake in fibrocystic disease was more prominent with FDG than with TYR. No difference in tumor/nontumor ratio between the two tracers could be established. FDG showed a false-positive result in one benign lesion. No major differences between the SUVs as defined above were found, although the best correlation between glucose consumption and the SUV was observed when the SUV was based on body surface area and corrected for plasma glucose level (r = 0.85-0.87). The SUV based on lean body mass was found to correlate best with protein synthesis rate (r = 0.83-0.94). CONCLUSION: In this group of patients, TYR appears to be a better tracer than FDG for breast cancer imaging, because of lower uptake in fibrocystic disease. SUVs correlate well with quantitative values, but future studies must determine whether treatment evaluation is also reliable with SUVs.
- 171Plaat, B.; Kole, A.; Mastik, M.; Hoekstra, H.; Molenaar, W.; Vaalburg, W. Protein synthesis rate measured with L-[1–11C]tyrosine positron emission tomography correlates with mitotic activity and MIB-1 antibody-detected proliferation in human soft tissue sarcomas. Eur. J. Nucl. Med. Mol. Imaging 1999, 26, 328– 332, DOI: 10.1007/s002590050394
- 172Braams, J. W.; Pruim, J.; Nikkels, P. G.; Roodenburg, J. L.; Vaalburg, W.; Vermey, A. Nodal spread of squamous cell carcinoma of the oral cavity detected with PET-tyrosine, MRI and CT. J. Nucl. Med. 1996, 37, 897– 901[PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK28zgtVentQ%253D%253D&md5=1a9c95b4de9ce0c4855b11586b5a0533Nodal spread of squamous cell carcinoma of the oral cavity detected with PET-tyrosine, MRI and CTBraams J W; Pruim J; Nikkels P G; Roodenburg J L; Vaalburg W; Vermey AJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1996), 37 (6), 897-901 ISSN:0161-5505.UNLABELLED: The uptake of L-1-[11C]-tyrosine (TYR) in cervical lymph nodes of eleven patients with squamous-cell carcinoma (SCC) of the oral cavity was studied with PET to detect lymphogenic metastases. METHODS: The TYR-PET results were compared with clinical, MRI, CT, histopathologic findings and historical data of patients studied with FDG. Sensitivity, specificity, accuracy and the positive and negative predictive values were calculated. RESULTS: TYR-PET had sensitivity of 83% and a specificity of 95%. In contrast, the sensitivity and specificity for MRI were 33% and 96%, respectively. The sensitivity and specificity for CT were 55% and 91%, respectively. TYR-PET results compared favorably with FDG. CONCLUSION: With TYR-PET, SCC metastases of the oral cavity can be visualized with high sensitivity and specificity. TYR-PET can be an additional tool for further evaluation of neck malignancies.
- 173Juhász, C.; Muzik, O.; Chugani, D. C.; Chugani, H. T.; Sood, S.; Chakraborty, P. K.; Barger, G. R.; Mittal, S. Differential kinetics of α-[11C]methyl-L-tryptophan on PET in low-grade brain tumors. J. Neuro-Oncol. 2011, 102, 409– 415, DOI: 10.1007/s11060-010-0327-1[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlslCntb0%253D&md5=651dd82c2ef47d8a2fb4d98be3efb820Differential kinetics of α-[11C]methyl-l-tryptophan on PET in low-grade brain tumorsJuhasz, Csaba; Muzik, Otto; Chugani, Diane C.; Chugani, Harry T.; Sood, Sandeep; Chakraborty, Pulak K.; Barger, Geoffrey R.; Mittal, SandeepJournal of Neuro-Oncology (2011), 102 (3), 409-415CODEN: JNODD2; ISSN:0167-594X. (Springer)Increased tryptophan metab. via the kynurenine pathway is a major mechanism of tumor immuno-resistance. α-[11C]Methyl-l-tryptophan (AMT) is a positron emission tomog. (PET) tracer for tryptophan catabolism, and increased AMT uptake has been demonstrated in brain tumors. In this study we evaluated the use of AMT PET for detection of low-grade gliomas and glioneuronal tumors, and detd. if kinetic parameters of AMT uptake can differentiate among tumor types. AMT PET images were obtained in 23 patients with newly diagnosed low-grade brain tumors (WHO grade II gliomas and WHO grade I dysembryoplastic neuroepithelial tumors [DNETs]). Kinetic variables, including the unidirectional uptake rate (K-complex) and vol. of distribution (VD; which characterizes tracer transport), were measured using a graphical approach from tumor dynamic PET and blood-input data, and metabolic rates () were also calcd. These values as well as tumor/cortex ratios were compared across tumor types. AMT PET showed increased tumor/cortex K-complex (n = 16) and/or VD ratios (n = 15) in 21/23 patients (91%), including 11/13 tumors with no gadolinium enhancement on MRI. No increases in AMT were seen in an oligodendroglioma and a DNET. Astrocytomas and oligoastrocytomas showed higher tumor/cortex ratios (1.66 ± 0.46) than oligodendrogliomas (0.96 ± 0.21; P = 0.001) and DNETs (0.75 ± 0.39; P < 0.001). These results demonstrate that AMT PET identifies most low-grade gliomas and DNETs by high uptake, even if these tumors are not contrast-enhancing on MRI. Kinetic anal. of AMT uptake shows significantly higher tumor/cortex tryptophan metabolic ratios in astrocytomas and oligoastrocytomas in comparison with oligodendrogliomas and DNETs.
- 174Diksic, M.; Nagahiro, S.; Chaly, T.; Sourkes, T. L.; Yamamoto, Y. L.; Feindel, W. Serotonin synthesis rate measured in living dog brain by positron emission tomography. J. Neurochem. 1991, 56, 153– 162, DOI: 10.1111/j.1471-4159.1991.tb02575.x[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlsFymtg%253D%253D&md5=0c131f09f5438dc40dbf80c6540ae92bSerotonin synthesis rate measured in living dog brain by positron emission tomographyDiksic, M.; Nagahiro, S.; Chaly, T.; Sourkes, T. L.; Yamamoto, Y. L.; Feindel, W.Journal of Neurochemistry (1991), 56 (1), 153-62CODEN: JONRA9; ISSN:0022-3042.In vivo measurements by positron emission tomog. of the brain 5-HT synthesis rates in the normal dog, in the dog with increased plasma tryptophan concn., and in the dog under different arterial O tensions are described. This method permits repeated measurements in the same brain for the first time. An increase in the plasma tryptophan concn. from 16.6 to 191.5 and then to 381 μM resulted in close to a linear increase in the brain 5-HT synthesis rate. When PaO2 was raised from 76 to 106 mm Hg, the rate of 5-HT synthesis in the dog brain increased from 39 to 54 pmol/g/min. The ests. of the Michaelis-Menten consts., Kmapp and Vmax, for the transport of tryptophan through the blood-brain barrier are 303 μM and 63 nmol/g/min, resp.
- 175Diksic, M.; Nagahiro, S.; Sourkes, T. L.; Yamamoto, Y. L. A new method to measure brain serotonin synthesis in vivo. I. theory and basic data for a biological model. J. Cereb. Blood Flow Metab. 1990, 10, 1– 12, DOI: 10.1038/jcbfm.1990.1[Crossref], [PubMed], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhslagu7Y%253D&md5=520e54d1be3e4e699996a58cbb63f5ddA new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological modelDiksic, M.; Nagahiro, S.; Sourkes, T. L.; Yamamoto, Y. L.Journal of Cerebral Blood Flow and Metabolism (1990), 10 (1), 1-12CODEN: JCBMDN; ISSN:0271-678X.An autoradiog. method to measure the in vivo rate of serotonin synthesis in rat brain is described. The method is based on the use of the L-tryptophan analog α-methyl-L-tryptophan (α-MTrp), which is converted in vivo into α-methylserotonin (α-M5HT). Since α-M5HT is not a substrate for monoamine oxidase, it is accumulated in the brain tissue. Data are presented to confirm time-dependent conversion of α-MTrp into α-M5HT in the dorsal raphe nucleus and also in the pineal body, an organ outside the blood-brain barrier. Washing of brain slices in 10% TCA resulted in <3% incorporation of α-MTrp into brain proteins. The rates of synthesis are calcd. in several grossly dissected brain structures by using tracer kinetics and a 3-compartment biol. model. The half-life of the precursor pool is ∼20 min. The rate of serotonin synthesis is highest in the pineal body.
- 176Diksic, M.; Tohyama, Y.; Takada, A. Brain net unidirectional uptake of alpha-[14C]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp. Neurochem. Res. 2000, 25, 1537– 1546, DOI: 10.1023/A:1026654116999[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovFyhtrs%253D&md5=f170a9fc6e5df59e7b7e78a06f4165b4Brain net unidirectional uptake of α-[14C]methyl-L-tryptophan (α-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and α-MTrpDiksic, Mirko; Tohyama, Yoshihiro; Takada, AkiraNeurochemical Research (2000), 25 (12), 1537-1546CODEN: NEREDZ; ISSN:0364-3190. (Kluwer Academic/Plenum Publishers)The uptake and trapping consts. for labeled tryptophan (Trp) via the serotonin (5-hydroxytryptamine; 5-HT) metabolic pathway and for the incorporation of Trp into proteins, and α-[14C]methyl-L-tryptophan (α-MTrp) were measured. Measurements were done in rats treated with either saline or probenecid (200 mg/kg). In addn., the blood-brain barrier (BBB) permeability surface area products for Trp (PST) and α-MTrp (PSα) were measured in normal rats. The results suggest that, in both groups of rats, there is a highly significant correlation (Pearson Product Moment Correlation (PPMC)) between the brain uptake and trapping consts. for α-MTrp and those of Trp via the 5-HT metabolic pathway, but there is no significant correlation (PPMC) between either of these consts. and the PS products of either compd. There is also no significant correlation (PPMC) between the const. for the Trp incorporation into proteins with any of the other parameters. For all parameters, except Trp incorporation into proteins (α-MTrp is not incorporated into proteins), there was a highly significant correlation between the quantities measured for Trp and α-MTrp. The data presented here strongly suggests that the brain uptake and trapping of α-MTrp relates to brain 5-HT synthesis, and does not relate to the BBB transport or protein incorporation of Trp. On the basis of these results, as well as those previously reported, the authors concluded that trapping (unidirectional uptake) of α-MTrp can be converted to the 5-HT synthesis rates in the brain. From this also follows that labeled α-MTrp is a good tracer for in vivo evaluation of the brain 5-HT synthesis.
- 177Muzik, O.; Chugani, D. C.; Chakraborty, P.; Mangner, T.; Chugani, H. T. Analysis of [C-11]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivo. J. Cereb. Blood Flow Metab. 1997, 17, 659– 669, DOI: 10.1097/00004647-199706000-00007[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlsVGiurk%253D&md5=bca7d213d43039028a16eb43ea771cadAnalysis of [11C]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivoMuzik, Otto; Chugani, Diane C.; Chakraborty, Pulak; Mangner, Thomas; Chugani, Harry T.Journal of Cerebral Blood Flow and Metabolism (1997), 17 (6), 659-669CODEN: JCBMDN; ISSN:0271-678X. (Lippincott-Raven)The authors describe the tracer kinetic anal. of [C-11]-labeled alpha-methyl-tryptophan (AMT), an analog of tryptophan, which has been developed as a tracer for serotonin synthesis using positron emission tomog. (PET) in human brain. Dynamic PET data were acquired from young healthy volunteers as a series of 22 scans covering a total of 60 min and analyzed by a three-compartment, four-parameter model. In addn., functional images of the K-complex were created using the Patlak-plot approach. The application of a three-compartment model resulted in low identifiability of individual k-values, esp. that of k3. Model identifiability anal. using a singular value decompn. of the final sensitivity matrix showed parameter identifiability to increase by 50% when the Patlak-plot approach was used. K-complex values derived by the Patlak-plot approach overestimated the compartmental values by 10 to 20%, because of the violation of the dynamic equil. assumption. However, this bias was fairly const. in all structures of the brain. The rank order of K-complex values from different brain regions corresponded well to the regional concns. of serotonin in human brain. These results indicate that the Patlak-plot method can be readily applied to [C-11]AMT data to create functional images of the K-complex, reflecting serotonin synthesis rate, within an acceptable error margin.
- 178Chugani, D. C.; Chugani, H. T.; Muzik, O.; Shah, J. R.; Shah, A. K.; Canady, A.; Mangner, T. J.; Chakraborty, P. K. Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. Ann. Neurol. 1998, 44, 858– 866, DOI: 10.1002/ana.410440603[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M%252Fms1Omtg%253D%253D&md5=4d640553dbbb23d60b8f7f09002e3c68Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomographyChugani D C; Chugani H T; Muzik O; Shah J R; Shah A K; Canady A; Mangner T J; Chakraborty P KAnnals of neurology (1998), 44 (6), 858-66 ISSN:0364-5134.Several reports have indicated that cortical resection is effective in alleviating intractable epilepsy in children with tuberous sclerosis complex (TSC). Because of the multitude of cortical lesions, however, identifying the epileptogenic tuber(s) is difficult and often requires invasive intracranial electroencephalographic (EEG) monitoring. As increased concentrations of serotonin and serotonin-immunoreactive processes have been reported in resected human epileptic cortex, we used alpha-[11C]methyl-L-tryptophan ([11C]AMT) positron emission tomography (PET) to test the hypothesis that serotonin synthesis is increased interictally in epileptogenic tubers in patients with TSC. Nine children with TSC and epilepsy, aged 1 to 9 years (mean, 4 years 1 month), were studied. All children underwent scalp video-EEG monitoring, PET scans of glucose metabolism and serotonin synthesis, and EEG monitoring during both PET studies. [11C]AMT scans were coregistered with magnetic resonance imaging and with glucose metabolism scans. Whereas glucose metabolism PET showed multifocal cortical hypometabolism corresponding to the locations of tubers in all 9 children, [11C]AMT uptake was increased in one tuber (n=3), two tubers (n=3), three tubers (n=1), and four tubers (n=1) in 8 of the 9 children. All other tubers showed decreased [11C]AMT uptake. Ictal EEG data available in 8 children showed seizure onset corresponding to foci of increased [11C]AMT uptake in 4 children (including 2 with intracranial EEG recordings). In 2 children, ictal EEG was nonlocalizing, and in 1 child there was discordance between the region of increased [11C]AMT uptake and the region of ictal onset on EEG. The only child whose [11C]AMT scan showed no regions of increased uptake had a left frontal seizure focus on EEG; however, at the time of his [11C]AMT PET scan, his seizures had come under control. [11C]AMT PET may be a powerful tool in differentiating between epileptogenic and nonepileptogenic tubers in patients with TSC.
- 179Chugani, H. T.; Luat, A. F.; Kumar, A.; Govindan, R.; Pawlik, K.; Asano, E. α-[11C]-methyl-L-tryptophan-PET in 191 patients with tuberous sclerosis complex. Neurology 2013, 81, 674– 680, DOI: 10.1212/WNL.0b013e3182a08f3f[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1OqtLbO&md5=43c3ad9e55942d0536b222aa1df01dc4α-[11C]-Methyl-L-tryptophan-PET in 191 patients with tuberous sclerosis complexChugani, Harry T.; Luat, Aimee F.; Kumar, Ajay; Govindan, Rajkumar; Pawlik, Kathy; Asano, EishiNeurology (2013), 81 (7), 674-680CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objectives: This was an observational study done on a large cohort of patients with tuberous sclerosis complex (TSC) to det. whether (i) the presence of α-[C]-methyl-L-tryptophan (AMT) hotspots is related to the duration of seizure intractability, (ii) the presence of AMT hotspots is related to specific TSC gene mutations, and (iii) there is concordance between areas with an AMT hotspot and seizure lateralization/localization on scalp EEG. Methods: One hundred ninety-one patients (mean age: 6.7 years; median: 5 years; range: 3 mo to 37 years) with TSC and intractable epilepsy were included. All patients underwent AMT-PET scan. AMT uptake in each tuber and normal-appearing cortex was measured and correlated with clin., scalp EEG, and, if available, electrocorticog. data. Results: The longer the duration of seizure intractability, the greater the no. of AMT hotspots (r = 0.2; p = 0.03). AMT hotspots were seen in both TSC1 and TSC2. There was excellent agreement in seizure focus lateralization between ictal scalp EEG and AMT-PET (Cohen κ 0.94) in 68 of 95 patients in whom both ictal video-EEG and AMT-PET showed lateralizing findings; in 28 of 68 patients (41%), AMT was more localizing. Furthermore, AMT-PET was localizing in 10 of 17 patients (58%) with nonlateralized ictal EEG. Conclusion: AMT-PET, when used together with video-EEG, provides addnl. lateralization/localization data, regardless of TSC mutation. The duration of seizure intractability may predict the multiplicity of areas with AMT hotspots.
- 180Juhasz, C.; Chugani, D. C.; Muzik, O.; Shah, A.; Asano, E.; Mangner, T. J.; Chakraborty, P. K.; Sood, S.; Chugani, H. T. Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 2003, 60, 960– 968, DOI: 10.1212/01.WNL.0000049468.05050.F2[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7ktVKqsA%253D%253D&md5=95568b7095b1b1c8ec5c934a67f7fbadAlpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsyJuhasz C; Chugani D C; Muzik O; Shah A; Asano E; Mangner T J; Chakraborty P K; Sood S; Chugani H TNeurology (2003), 60 (6), 960-8 ISSN:.BACKGROUND: In children with tuberous sclerosis, the PET tracer alpha[11C]methyl-L-tryptophan (AMT) has been shown to be selectively taken up by epileptogenic tubers, thus allowing differentiation from nonepileptogenic tubers in the interictal state. OBJECTIVE: To determine whether cortical areas showing increased AMT uptake in children without tuberous sclerosis complex with intractable neocortical epilepsy indicate the epileptogenic zone, and to assess the relative contributions of AMT and 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET abnormalities to the localization of epileptogenic cortical regions. METHODS: Areas of increased AMT and decreased FDG uptake were marked objectively as regions with abnormal asymmetry using an in-house written software in 27 children who underwent comprehensive evaluation for resective epilepsy surgery. The marked PET abnormalities were compared to the locations of scalp and subdural EEG epileptiform abnormalities, as well as histology and surgical outcome. RESULTS: Focal cortical increases of AMT uptake were found in 15 patients. The lobar sensitivity (39.0%) of AMT PET for seizure onset was lower, but its specificity (100%) was higher (p < 0.0001) than that of hypometabolism on FDG PET (sensitivity 73.2%, specificity 62.7%). AMT PET abnormalities were smaller than corresponding FDG PET hypometabolic regions (p = 0.002), and increased AMT uptake occurred in two patients with nonlocalizing FDG PET. Histologically verified cortical developmental malformations were associated with increased AMT uptake (p = 0.044). Subdural electrodes adjacent to the area of increased AMT uptake were most often involved in seizure onset. CONCLUSIONS: Focal increase of cortical AMT uptake in children is less sensitive but more specific for the lobe of seizure onset than corresponding FDG PET hypometabolism, and it is often associated with epileptogenic cortical developmental malformations. AMT PET can assist placement of subdural electrodes even when MRI and FDG PET fail to provide adequate localizing information. Cortical areas adjacent to increased AMT uptake should be carefully addressed by intracranial EEG because these regions often show a high degree of epileptogenicity.
- 181Juhasz, C.; Chugani, D. C.; Padhye, U. N.; Muzik, O.; Shah, A.; Asano, E.; Mangner, T. J.; Chakraborty, P. K.; Sood, S.; Chugani, H. T. Evaluation with alpha-[11C]methyl-l-tryptophan positron emission tomography for reoperation after failed epilepsy surgery. Epilepsia 2004, 45, 124– 130, DOI: 10.1111/j.0013-9580.2004.30303.x[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c%252FjvFCjtQ%253D%253D&md5=f04dcbbec356603b71bbd94fcd4b723cEvaluation with alpha-[11C]methyl-L-tryptophan positron emission tomography for reoperation after failed epilepsy surgeryJuhasz Csaba; Chugani Diane C; Padhye Uma N; Muzik Otto; Shah Aashit; Asano Eishi; Mangner Tom J; Chakraborty Pulak K; Sood Sandeep; Chugani Harry TEpilepsia (2004), 45 (2), 124-30 ISSN:0013-9580.PURPOSE: Reoperation after failed cortical resection can alleviate seizures in patients with intractable neocortical epilepsy, provided that previously nonresected epileptic regions are accurately defined and removed. Most imaging modalities have limited value in identifying such regions after a previous surgery. Positron emission tomography (PET) using alpha-[11C]methyl-L-tryptophan (AMT) can detect epileptogenic cortical areas as regions with increased tracer uptake. This study analyzed whether increased cortical AMT uptake can detect nonresected epileptic foci in patients with previously failed neocortical resection. METHODS: Thirty-three young patients (age 3-26 years; mean age, 10.8 years) with intractable epilepsy of neocortical origin, and a previously failed cortical resection performed at various epilepsy centers, underwent further presurgical evaluation for reoperation. AMT-PET scans were performed 6 days to 7 years after the first surgery. Focal cortical areas with increased AMT uptake were objectively identified and correlated to ictal EEG data as well as clinical variables (age, postsurgical time, etiology). RESULTS: Cortical increases of AMT uptake were detected on the side of the previous resections in 12 cases. In two patients scanned shortly (within a week) after surgery, diffuse hemispheric increases were observed, without any further localization value. In contrast, in 10 (43%) of 23 patients scanned >2 months but within 2.3 years after surgery, focal cortical increases occurred, concordant with seizure onset on ictal EEG. Age, etiology (lesional vs. cryptogenic), epileptiform EEG activity during PET, or time of the last seizure were not significantly related to the presence of increased AMT uptake. All patients with localizing AMT-PET, who underwent reoperation, became seizure free (n = 5) or showed considerable improvement of seizure frequency (n = 2). CONCLUSIONS: AMT-PET can identify nonresected epileptic cortex in patients with a previously failed neocortical epilepsy surgery and, with proper timing for the scan, can assist in planning reoperation.
- 182Chen, Y.; Guillemin, G. J. Kynurenine pathway metabolites in humans: Disease and healthy states. Int. J. Tryptophan Res. 2009, 2, IJTR.S2097, DOI: 10.4137/IJTR.S2097
- 183Uyttenhove, C.; Pilotte, L.; Théate, I.; Stroobant, V.; Colau, D.; Parmentier, N.; Boon, T.; Van den Eynde, B. J. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 2003, 9, 1269– 1274, DOI: 10.1038/nm934[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXns1Clu7c%253D&md5=c2be3620862064fb40da547f976ccf95Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenaseUyttenhove, Catherine; Pilotte, Luc; Theate, Ivan; Stroobant, Vincent; Colau, Didier; Parmentier, Nicolas; Boon, Thierry; Van den Eynde, Benoit J.Nature Medicine (New York, NY, United States) (2003), 9 (10), 1269-1274CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)T lymphocytes undergo proliferation arrest when exposed to tryptophan shortage, which can be provoked by indoleamine 2,3-dioxygenase (IDO), an enzyme that is expressed in placenta and catalyzes tryptophan degrdn. Here we show that most human tumors constitutively express IDO. We also obsd. that expression of IDO by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.
- 184Juhász, C.; Dwivedi, S.; Kamson, D. O.; Michelhaugh, S. K.; Mittal, S. Comparison of amino acid positron emission tomographic radiotracers for molecular imaging of primary and metastatic brain tumors. Mol. Imaging 2014, 13, 7290.2014.00015, DOI: 10.2310/7290.2014.00015
- 185Alkonyi, B.; Barger, G. R.; Mittal, S.; Muzik, O.; Chugani, D. C.; Bahl, G.; Robinette, N. L.; Kupsky, W. J.; Chakraborty, P. K.; Juhasz, C. Accurate differentiation of recurrent gliomas from radiation injury by kinetic analysis of −11C-methyl-L-tryptophan PET. J. Nucl. Med. 2012, 53, 1058– 1064, DOI: 10.2967/jnumed.111.097881[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1ajtrvI&md5=d10cd5f37876861f8a84af5d9f48c521Accurate differentiation of recurrent gliomas from radiation injury by kinetic analysis of α-11C-methyl-L-tryptophan PETAlkonyi, Balint; Barger, Geoffrey R.; Mittal, Sandeep; Muzik, Otto; Chugani, Diane C.; Bahl, Gautam; Robinette, Natasha L.; Kupsky, William J.; Chakraborty, Pulak K.; Juhasz, CsabaJournal of Nuclear Medicine (2012), 53 (7), 1058-1064CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)PET of amino acid transport and metab. may be more accurate than conventional neuroimaging in differentiating recurrent gliomas from radiation-induced tissue changes. α-11C-methyl-L-tryptophan (11C-AMT) is an amino acid PET tracer that is not incorporated into proteins but accumulates in gliomas, mainly because of tumoral transport and metab. via the immunomodulatory kynurenine pathway. The aim of this study was to evaluate the usefulness of 11C-AMT PET supplemented by tracer kinetic anal. for distinguishing recurrent gliomas from radiation injury. Methods: Twenty-two 11C-AMT PET scans were obtained in adult patients who presented with a lesion suggestive of tumor recurrence on conventional MR11-6 y (mean, 3 y) after resection and postsurgical radiation of a World Health Organization grade II-IV glioma. Lesional standardized uptake values were calcd., as well as lesion-to-contralateral cortex ratios and 2 kinetic 11C-AMT PET parameters (vol. of distribution [VD], characterizing tracer transport, and unidirectional uptake rate [K]). Tumor was differentiated from radiation-injured tissue by histopathol. (n = 13) or 1-y clin. and MRI follow-up (n = 9). Accuracy of tumor detection by PET variables was assessed by receiver-operating-characteristic anal. Results: All 11C-AMT PET parameters were higher in tumors (n = 12) than in radiation injury (n = 10) (P ≤ 0.012 in all comparisons). The lesion-to-cortex K-ratio most accurately identified tumor recurrence, with highly significant differences both in the whole group (P < 0.0001) and in lesions with histol. verification (P = 0.006); the area under the receiver-operating-characteristic curve was 0.99. A lesion-to-cortex K-ratio threshold of 1.39 (i.e., a 39% increase) correctly differentiated tumors from radiation injury in all but 1 case (100% sensitivity and 91% specificity). In tumors that were high-grade initially (n = 15), a higher lesion-to-cortex K-ratio threshold completely sepd. recurrent tumors (all K-ratios ≥ 1.70) from radiation injury (all K-ratios < 1.50) (100% sensitivity and specificity). Conclusion: Kinetic anal. of dynamic 11C-AMT PET images may accurately differentiate between recurrent World Health Organization grade II-IV infiltrating gliomas and radiation injury. Sepn. of unidirectional uptake rates from transport can enhance the differentiating accuracy of 11C-AMT PET. Applying the same approach to other amino acid PET tracers might also improve their ability to differentiate recurrent gliomas from radiation injury.
- 186Miettinen, H.; Kononen, J.; Haapasalo, H.; Helén, P.; Sallinen, P.; Harjuntausta, T.; Helin, H.; Alho, H. Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: Relationship to cell proliferation. Cancer Res. 1995, 55, 2691– 2695[PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmtlWrt7Y%253D&md5=86e765d3b788beced8ed2207ea54c977Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferationMiettinen, Helena; Kononen, Juha; Haapasalo, Hannu; Hel´en, Pauli; Sallinen, Pauli; Harjuntausta, Tero; Helin, Heikki; Alho, HannuCancer Research (1995), 55 (12), 2691-5CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The expression of peripheral-type benzodiazepine receptor (PBR) and diazepam binding inhibitor (DBI) were studied in human astrocytic tumors using immunocytochem. and in situ hybridization. Both PBR and DBI were prominently expressed in neoplastic cells, whereas in normal brain their amt. was low or undetectable. Immunocytochem. double straining demonstrated that PBR and DBI were present in the same cells, suggesting the DBI may act in an autocrine manner in these cells. Anal. of 86 cases showed that PBR expression was statistically significantly assocd. with tumor malignancy grade (P = 0.004) and the proliferative index as detd. by immunocytochem. with the MIB-1 antibody (P = 0.004). Patients having tumors with high levels of PBR-immunoreactive cells had a shorter life expectancy than patients whose tumors showed lower PBR contents (P = 0.024). In conclusion, these results show that PBR expression is higher in neoplastic cells than in normal brain tissue. They also suggest that PBR immunocytochem. might be useful in evaluating malignancy in brain tumors.
- 187Vlodavsky, E.; Soustiel, J. F. Immunohistochemical expression of peripheral benzodiazepine receptors in human astrocytomas and its correlation with grade of malignancy, proliferation, apoptosis and survival. J. Neuro-Oncol. 2006, 81, 1– 7, DOI: 10.1007/s11060-006-9199-9
- 188Su, Z.; Roncaroli, F.; Durrenberger, P. F.; Coope, D. J.; Karabatsou, K.; Hinz, R.; Thompson, G.; Turkheimer, F. E.; Janczar, K.; Du Plessis, D.; Brodbelt, A.; Jackson, A.; Gerhard, A.; Herholz, K. The 18-kDa mitochondrial translocator protein in human gliomas: An 11C-(R)PK11195 PET imaging and neuropathology study. J. Nucl. Med. 2015, 56, 512– 517, DOI: 10.2967/jnumed.114.151621[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmvVWmtLg%253D&md5=0eab0b842853bbdf86eb0f2275058d3fThe 18-kDa mitochondrial translocator protein in human gliomas: an 11C-(R)PK11195 PET imaging and neuropathology studySu, Zhangjie; Roncaroli, Federico; Durrenberger, Pascal F.; Coope, David J.; Karabatsou, Konstantina; Hinz, Rainer; Thompson, Gerard; Turkheimer, Federico E.; Janczar, Karolina; Du Plessis, Daniel; Brodbelt, Andrew; Jackson, Alan; Gerhard, Alexander; Herholz, KarlJournal of Nuclear Medicine (2015), 56 (4), 512-517CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)The 18-kDa mitochondrial translocator protein (TSPO) is upregulated in high-grade astrocytomas and can be imaged by PET using the selective radiotracer 11C-(R)PK11195. We investigated 11C-(R)PK11195 binding in human gliomas and its relationship with TSPO expression in tumor tissue and glioma-assocd. microglia/macrophages (GAMs) within the tumors. Methods: Twenty-two glioma patients underwent dynamic 11C-(R)PK11195 PET scans and perfusion MR imaging acquisition. Parametric maps of 11C-(R)PK11195 binding potential (BPND) were generated. Co-registered MR/PET images were used to guide tumor biopsy. The tumor tissue was quant. assessed for TSPO expression and infiltration of GAMs using immunohistochem. and double immunofluorescence. The imaging and histopathol. parameters were compared among different histotypes and grades and correlated with each other. Results: BPND of 11C-(R)PK11195 in high-grade gliomas was significantly higher than in low-grade astrocytomas and low-grade oligodendrogliomas. TSPO in gliomas was expressed predominantly by neoplastic cells, and its expression correlated pos. with BPND in the tumors. GAMs only partially contributed to the overall TSPO expression within the tumors, and TSPO expression in GAMs did not correlate with tumor BPND. Conclusion: PET with 11C-(R)PK11195 in human gliomas predominantly reflects TSPO expression in tumor cells. It therefore has the potential to effectively stratify patients who are suitable for TSPO-targeted treatment.
- 189Junck, L.; Olson, J. M. M.; Ciliax, B. J.; Koeppe, R. A.; Watkins, G. L.; Jewett, D. M.; McKeever, P. E.; Wieland, D. M.; Kilbourn, M. R.; Starosta-Rubinstein, S.; Mancini, W. R.; Kuhl, D. E.; Greenberg, H. S.; Young, A. B. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann. Neurol. 1989, 26, 752– 758, DOI: 10.1002/ana.410260611[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhtFCqtbk%253D&md5=b9546f8a15368e8381576cdc3f5aabfaPET imaging of human gliomas with ligands for the peripheral benzodiazepine binding siteJunck, Larry; Olson, James M. M.; Ciliax, Brian J.; Koeppe, Robert A.; Watkins, G. Leonard; Jewett, Douglas M.; McKeever, Paul E.; Wieland, Donald M.; Kilbourn, Michael R.; et al.Annals of Neurology (1989), 26 (6), 752-8CODEN: ANNED3; ISSN:0364-5134.Human gliomas were imaged in vivo using ligands for the peripheral-type benzodiazepine binding site (or ω3 binding site) and positron emission tomog. (PET). Although gliomas have a high d. of the peripheral-type benzodiazepine binding site, PET scans with a selective ligand for this site, [11C]Ro5-4864, failed to demonstrate higher radioactivity levels in human gliomas than in brain. In vitro studies of surgically removed specimens of human glioma demonstrated little binding of Ro5-4864 but high levels of binding of another selective ligand, PK 11195. Scans with [11C]PK 11195 demonstrated increased radioactivity in glioma compared to brain in 8 of 10 patients. Radioactivity in tumor and the ratios of radioactivity in tumor to that in remote gray and in white matter correlated significantly with the specific activity of [11C]PK 11195, suggesting that accumulation represents saturable high-affinity binding. Thus, PK 11195 manifests greater binding than Ro5-4864 to the peripheral-type benzodiazepine binding site on human gliomas, and human gliomas can be successfully imaged using [11C]PK 11195 and PET.
- 190Pappata, S.; Cornu, P.; Samson, Y.; Prenant, C.; Benavides, J.; Scatton, B.; Crouzel, C.; Hauw, J. J.; Syrota, A. PET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: A case report. J. Nucl. Med. 1991, 32, 1608– 1610[PubMed], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3Mzjt1Oitw%253D%253D&md5=cd014a471a37f2b8a7153960231aa36aPET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: a case reportPappata S; Cornu P; Samson Y; Prenant C; Benavides J; Scatton B; Crouzel C; Hauw J J; Syrota AJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1991), 32 (8), 1608-10 ISSN:0161-5505.The utility of the peripheral type benzodiazepine site ligand 11C-PK 11195, for imaging human glioma in conjunction with Positron Emission Tomography, relies on a high specific binding of the tracer to tumoral peripheral type benzodiazepines sites. In a patient with glioblastoma, we found that 11C-PK 11195 binding was two-fold higher in the tumor than in normal gray matter and that 30% of tumoral binding could be displaced by a large excess of unlabeled drug. These findings suggest that tumoral retention of the ligand is due, in part, to specific binding.
- 191Roncaroli, F.; Su, Z.; Herholz, K.; Gerhard, A.; Turkheimer, F. E. TSPO expression in brain tumours: Is TSPO a target for brain tumour imaging?. Clin Transl Imaging. 2016, 4, 145– 156, DOI: 10.1007/s40336-016-0168-9[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FhtFKhtA%253D%253D&md5=c5766dd4a5305f8db0633cd58b0d1142TSPO expression in brain tumours: is TSPO a target for brain tumour imaging?Roncaroli Federico; Su Zhangjie; Herholz Karl; Gerhard Alexander; Turkheimer Federico EClinical and translational imaging (2016), 4 (), 145-156 ISSN:2281-5872.Positron emission tomography (PET) alone or in combination with MRI is increasingly assuming a central role in the development of diagnostic and therapeutic strategies for brain tumours with the aim of addressing tumour heterogeneity, assisting in patient stratification, and contributing to predicting treatment response. The 18 kDa translocator protein (TSPO) is expressed in high-grade gliomas, while its expression is comparatively low in normal brain. In addition, the evidence of elevated TSPO in neoplastic cells has led to studies investigating TSPO as a transporter of anticancer drugs for brain delivery and a selective target for tumour tissue. The TSPO therefore represents an ideal candidate for molecular imaging studies. Knowledge of the biology of TSPO in normal brain cells, in-depth understanding of TSPO functions and biodistribution in neoplastic cells, accurate methods for quantification of uptake of TSPO tracers and pharmacokinetic data regarding TSPO-targeted drugs are required before introducing TSPO PET and TSPO-targeted treatment in clinical practice. In this review, we will discuss the impact of preclinical PET studies and the application of TSPO imaging in human brain tumours, the advantages and disadvantages of TSPO imaging compared to other imaging modalities and other PET tracers, and pathology studies on the extent and distribution of TSPO in gliomas. The suitability of TSPO as molecular target for treatment of brain tumours will also be the appraised.
- 192Su, Z.; Herholz, K.; Gerhard, A.; Roncaroli, F.; Du Plessis, D.; Jackson, A.; Turkheimer, F.; Hinz, R. [11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 1406– 1419, DOI: 10.1007/s00259-013-2447-2[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1GmtbjK&md5=1ef1a7fa51991575e9d79e30113a83e8[11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approachesSu, Zhangjie; Herholz, Karl; Gerhard, Alexander; Roncaroli, Federico; Du Plessis, Daniel; Jackson, Alan; Turkheimer, Federico; Hinz, RainerEuropean Journal of Nuclear Medicine and Molecular Imaging (2013), 40 (9), 1406-1419CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: Translocator protein (TSPO) is a biomarker of neuroinflammation that can be imaged by PET using [11C]-(R)PK11195. We sought to characterize the [11C]-(R)PK11195 kinetics in gliomas of different histotypes and grades, and to compare two ref. tissue input functions (supervised cluster anal. vs. cerebellar gray matter) for the estn. of [11C]-(R)PK11195 binding in gliomas and surrounding brain structures. Methods: Twenty-three glioma patients and ten age-matched controls underwent structural MRI and dynamic [11C]-(R)PK11195 PET scans. Tissue time-activity curves (TACs) were extd. from tumor regions as well as gray matter (GM) and white matter (WM) of the brains. Parametric maps of binding potential (BPND) were generated with the simplified ref. tissue model using the two input functions, and were compared with each other. TSPO expression was assessed in tumor tissue sections by immunohistochem. Results: Three types of regional kinetics were obsd. in individual tumor TACs: GM-like kinetics (n = 6, clearance of the tracer similar to that in cerebellar GM), WM-like kinetics (n = 8, clearance of the tracer similar to that in cerebral WM) and a form of mixed kinetics (n = 9, intermediate rate of clearance). Such kinetic patterns differed between low-grade astrocytomas (WM-like kinetics) and oligodendrogliomas (GM-like and mixed kinetics), but were independent of tumor grade. There was good agreement between parametric maps of BPND derived from the two input functions in all controls and 10 of 23 glioma patients. In 13 of the 23 patients, BPND values derived from the supervised cluster input were systematically smaller than those using the cerebellar input. Immunohistochem. confirmed that TSPO expression increased with tumor grade. Conclusion: The three types of [11C]-(R)PK11195 kinetics in gliomas are detd. in part by tracer delivery, and indicated that kinetic anal. is a valuable tool in the study of gliomas with the potential for in vivo discrimination between low-grade astrocytomas and oligodendrogliomas. Supervised cluster and cerebellar input functions produced consistent BPND ests. in approx. half of the gliomas investigated, but had a systematic difference in the remainder. The cerebellar input is preferred based on theor. and practical considerations.
- 193Ashmore-Harris, C.; Iafrate, M.; Saleem, A.; Fruhwirth, G. O. Non-invasive reporter gene imaging of cell therapies, including T cells and stem cells. Mol. Ther. 2020, 28, 1392– 1416, DOI: 10.1016/j.ymthe.2020.03.016[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFSksLvN&md5=b28b160002f6de9ddf960f6e55a69a90Non-invasive Reporter Gene Imaging of Cell Therapies, including T Cells and Stem CellsAshmore-Harris, Candice; Iafrate, Madeleine; Saleem, Adeel; Fruhwirth, Gilbert O.Molecular Therapy (2020), 28 (6), 1392-1416CODEN: MTOHCK; ISSN:1525-0024. (Cell Press)Cell therapies represent a rapidly emerging class of new therapeutics. They are intended and developed for the treatment of some of the most prevalent human diseases, including cancer, diabetes, and for regenerative medicine. Currently, they are largely developed without precise assessment of their in vivo distribution, efficacy, or survival either clin. or preclinically. However, it would be highly beneficial for both preclin. cell therapy development and subsequent clin. use to assess these parameters in situ to enable enhancements in efficacy, applicability, and safety. Mol. imaging can be exploited to track cells non-invasively on the whole-body level and can enable monitoring for prolonged periods in a manner compatible with rapidly expanding cell types. In this review, we explain how in vivo imaging can aid the development and clin. translation of cell-based therapeutics. We describe the underlying principles governing non-invasive in vivo long-term cell tracking in the preclin. and clin. settings, including available imaging technologies, reporter genes, and imaging agents as well as pitfalls related to exptl. design. Our emphasis is on adoptively transferred T cell and stem cell therapies.
- 194Brader, P.; Serganova, I.; Blasberg, R. G. Noninvasive molecular imaging using reporter genes. J. Nucl. Med. 2013, 54, 167– 172, DOI: 10.2967/jnumed.111.099788[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlGks7g%253D&md5=247b4b1193ef6eb663a6fd40f45da5e2Noninvasive molecular imaging using reporter genesBrader, Peter; Serganova, Inna; Blasberg, Ronald G.Journal of Nuclear Medicine (2013), 54 (2), 167-172CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)A review. Noninvasive reporter gene imaging is a component of mol. imaging. Reporter imaging can provide noninvasive assessments of endogenous biol. processes in living subjects and can be performed using different imaging modalities. This review will focus on radionuclide-based reporter gene imaging as developed and applied in preclin. and clin. studies. Examples of different reporter systems are presented, with a focus on human reporter systems. Selected applications are discussed, including adoptive cell therapies, gene and oncoviral therapies, oncogenesis, signal pathway monitoring, and imaging drug treatment. Mol. imaging, and noninvasive reporter gene imaging in particular, are making important contributions to our understanding of disease development, progression, and treatment in our current era of mol. medicine and individualized patient care.
- 195Sellmyer, M. A.; Lee, I.; Hou, C.; Lieberman, B. P.; Zeng, C.; Mankoff, D. A.; Mach, R. H. Quantitative PET reporter gene imaging with [11C]trimethoprim. Mol. Ther. 2017, 25, 120– 126, DOI: 10.1016/j.ymthe.2016.10.018[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFCmtbo%253D&md5=9f42273c2b3a6c2b81dbc5028b66d1dcQuantitative PET Reporter Gene Imaging with [11C]TrimethoprimSellmyer, Mark A.; Lee, Iljung; Hou, Catherine; Lieberman, Brian P.; Zeng, Chenbo; Mankoff, David A.; Mach, Robert H.Molecular Therapy (2017), 25 (1), 120-126CODEN: MTOHCK; ISSN:1525-0024. (Cell Press)There is a need for improved methods to image genetically engineered cells, including immune cells used for cell-based therapy. Given the genetic manipulation inherent to gene therapy, the use of a reporter protein is a logical soln. and positron emission tomog. (PET) can provide the desired sensitivity and spatial localization. We developed a broadly applicable PET imaging strategy based on the small bacterial protein E. coli dihydrofolate reductase (Ec dhfr) and its highly specific small mol. inhibitor, trimethoprim (TMP). The difference in TMP affinity for bacterial compared to mammalian DHFR suggests that a TMP radioligand would have a low background in unmodified mammalian tissues and high retention in Ec dhfr engineered cells, providing high contrast imaging. Here, we describe the in vitro properties of [11C]TMP and show over 10-fold increased signal in transgenic Ec dhfr cells compared to control. In a mouse xenograft model, [11C]TMP rapidly accumulated in Ec dhfr carrying cells within minutes of i.v. administration. Moreover, [11C]TMP can identify less than a million xenografted cells in a small vol. in tissues other than the abdominal compartment. This limit of detection is a clin. relevant no. and bodes well for clin. translation esp. given that [11C]TMP is an isotopologue of clin. approved antibiotic.
- 196Grassi, I.; Nanni, C.; Allegri, V.; Morigi, J. J.; Montini, G. C.; Castellucci, P.; Fanti, S. The clinical use of PET with (11)C-acetate. Am. J. Nucl. Med. Mol. Imaging. 2012, 2, 33– 47[PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFOrtLY%253D&md5=2f1ef97bea8ca6c6b42b6c8d956b6398The clinical use of PET with 11C-acetateGrassi, Ilaria; Nanni, Cristina; Allegri, Vincenzo; Morigi, Joshua James; Montini, Gian Carlo; Castellucci, Paolo; Fanti, StefanoAmerican Journal of Nuclear Medicine and Molecular Imaging (2012), 2 (1), 33-47CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)The aim of this review is to evaluate clin. applications of 11C-acetate positron emission tomog. (PET). Acetate is quickly metabolized into acetyl-CoA in human cells. In this form it can either enter into the tricarboxylic acid cycle, thus producing energy, as happens in the myocardium, or participate in cell membrane lipid synthesis, as happens in tumor cells. 11C-acetate PET was originally employed in cardiol., to study myocardial oxygen metab. More recently it has also been used to evaluate myocardial perfusion, as well as in oncol. The first studies of 11C-acetate focused on its use in prostate cancer. Subsequently, 11C-acetate was studied in other urol. malignancies, as well as renal cell carcinoma and bladder cancer. Well differentiated hepatocellular carcinoma represents an 18F-fluoro-deoxyglucose (18F-FDG) PET pitfall, so many authors have proposed to use 11C-acetate in addn. to 18F-FDG in studying this tumor. 11C-acetate PET has also been used in other malignancies, such as brain tumors and lung carcinoma. Some authors reported a few cases in which 11C-acetate PET incidentally found multiple myeloma or rare tumors, such as thymoma, multicentric angiomyolipoma of the kidney and cerebellopontine angle schwannoma. Lastly, 11C-acetate PET was also employed in a differential diagnosis case between glioma and encephalitis. The numerous studies on 11C-acetate have demonstrated that it can be used in cardiol. and oncol. with no contraindications apart from pregnancy and the necessity of a rapid scan. Despite its limited availability, this tracer can surely be considered to be a promising one, because of its versatility and capacity to even detect non 18F-FDG-avid neoplasm, such as differentiated lung cancer or hepatocellular carcinoma.
- 197Brown, M.; Marshall, D. R.; Sobel, B. E.; Bergmann, S. R. Delineation of myocardial oxygen utilization with carbon-11-labeled acetate. Circulation 1987, 76, 687– 696, DOI: 10.1161/01.CIR.76.3.687[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2szgt1WlsA%253D%253D&md5=69acf224dbf5bdf7db867a49edf8e380Delineation of myocardial oxygen utilization with carbon-11-labeled acetateBrown M; Marshall D R; Sobel B E; Bergmann S RCirculation (1987), 76 (3), 687-96 ISSN:0009-7322.Although positron-emission tomography (PET) with labeled fatty acid delineates infarct size and permits qualitative assessment of fatty acid utilization, quantification of oxidative metabolism is limited by complex alterations in the pattern of utilization of fatty acid during ischemia and reperfusion. Because metabolism of acetate by myocardium is less complex than that of glucose or palmitate, we characterized kinetics of utilization of radiolabeled acetate in 37 isolated rabbit hearts perfused with modified Krebs-Henseleit buffer and performed a pilot tomographic study in man. Results of initial experiments with carbon-14-labeled acetate (14C-acetate) indicated that the steady-state extraction fraction of acetate averaged 61.5 +/- 4.0% in control hearts (n = 4), 93.6 +/- 0.9% in hearts rendered ischemic (n = 4), and 54.8 +/- 4.0% in hearts reperfused after 60 min of ischemia (n = 3). Oxidation of 14C-acetate, assessed from the rate of efflux of 14CO2 in the venous effluent, correlated closely with the rate of oxygen consumption under diverse metabolic conditions (r = .97, p less than .001). In addition, no significant differences were observed between rates of efflux of total 14C in all chemical species (reflecting total clearance of tracer from myocardium) and efflux of 14CO2. Clearance of 11C-acetate, measured externally with gamma probes in normal and ischemic myocardium, correlated closely with clearance of 14C-acetate measured directly in the effluent (r = .99, p less than .001) and with overall myocardial oxygen consumption (r = .95, p less than .001). Accumulation and clearance of 11C-acetate from human myocardium with PET demonstrated kinetics comparable to those seen with radiolabeled acetate in vitro. Thus externally detectable clearance of 11C-acetate provides a quantitative index of myocardial oxidative metabolism despite variation in the patterns of intermediary metabolism that confounds interpretation of results with conventionally used tracers such as glucose and fatty acid.
- 198Brown, M. A.; Myears, D. W.; Bergmann, S. R. Validity of estimates of myocardial oxidative metabolism with carbon-11 acetate and positron emission tomography despite altered patterns of substrate utilization. J. Nucl. Med. 1989, 30, 187– 193[PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M3ptlansA%253D%253D&md5=e9d95f6004f07a01565ba16a2223debbValidity of estimates of myocardial oxidative metabolism with carbon-11 acetate and positron emission tomography despite altered patterns of substrate utilizationBrown M A; Myears D W; Bergmann S RJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1989), 30 (2), 187-93 ISSN:0161-5505.We recently demonstrated that the myocardial turnover rate constant (k) measured noninvasively with positron emission tomography (PET) after intravenous administration of [11C]acetate provides a reliable index of myocardial oxidative metabolism (MVO2) theoretically independent of the pattern of myocardial substrate use. However, because estimates of metabolism with other metabolic tracers are sensitive to substrate use, we measured k in 12 dogs during baseline conditions and again after infusion of either glucose (n = 8) or Intralipid (n = 4), interventions that raised arterial glucose or fatty acids by more than fivefold with concomitant changes in myocardial substrate use. Following glucose administration k increased, but no difference was detected after compensation for changes in hemodynamics and myocardial work induced by the infusion (0.18 +/- 0.03 min-1 (t1/2 = 3.9 min) at baseline compared with 0.22 +/- 0.06 min-1 (t1/2 = 3.2 min, p = N.S.). k was not affected by Intralipid infusion (k = 0.15 +/- 0.06 min-1 at baseline and 0.14 +/- 0.04 min-1 during infusion), and correlated closely with MVO2 measured directly (n = 19 comparisons, r = 0.89). The results indicate that estimates of MVO2 using [11C]acetate and PET are valid despite changes in the pattern of myocardial substrate utilization.
- 199Beanlands, R. S.; Schwaiger, M. Changes in myocardial oxygen consumption and efficiency with heart failure therapy measured by 11C acetate PET. Can. J. Cardiol. 1995, 11, 293– 300[PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2M3ksF2jtQ%253D%253D&md5=81b20d1466f64677e4e5af5a422ff742Changes in myocardial oxygen consumption and efficiency with heart failure therapy measured by 11C acetate PETBeanlands R S; Schwaiger MThe Canadian journal of cardiology (1995), 11 (4), 293-300 ISSN:0828-282X.The application of 11C acetate kinetics determined by positron emission tomography (PET) imaging has been proposed as a noninvasive means to measure myocardial oxygen consumption in order to determine myocardial efficiency. Such an approach considers the balance of the effect of ventricular performance and myocardial oxygen consumption (MVO2), which may be important in the assessment of heart failure but is not usually evaluated by current methods. In this paper, the authors review their previously published series of studies, in which the aim was to: first, apply the 11C acetate PET approach in patients with dilated cardiomyopathy in order to determine myocardial oxidative metabolism and estimate myocardial efficiency; second, verify a correlation between 11C acetate kinetics and directly measured MVO2; and third, evaluate the effects of dobutamine and nitroprusside on MVO2 and efficiency in dilated cardiomyopathy. In these previous studies, 13 patients with severe dilated cardiomyopathy were studied, via echocardiography, hemodynamic and PET studies, at baseline and during drug infusion. Seven patients were given dobutamine and six were given nitroprusside. A two-compartment kinetic model approach was applied to 11C time activity curves obtained from dynamic 11C acetate PET imaging to determine the clearance rate constant, k2. Myocardial efficiency was estimated from a work metabolic index, defined as (stroke work index multiplied by heart rate) divided by k2. The k2 significantly increased with dobutamine (P < or = 0.05), consistent with increased MVO2, and tended to decrease with nitroprusside. The work metabolic index derived from hemodynamic parameters increased significantly with both drug regimens (P < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
- 200Kudo, T. Metabolic imaging using PET. Eur. J. Nucl. Med. Mol. Imaging 2007, 34 (S1), 49– 61, DOI: 10.1007/s00259-007-0440-3[Crossref], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVGgs7c%253D&md5=6226907f0de9d6c580d4488c32e185bbMetabolic imaging using PETKudo, TakashiEuropean Journal of Nuclear Medicine and Molecular Imaging (2007), 34 (Suppl. 1), S49-S61CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. Introduction: There is growing evidence that myocardial metab. plays a key role not only in ischemic heart disease but also in a variety of diseases which involve myocardium globally, such as heart failure and diabetes mellitus. Understanding myocardial metab. in such diseases helps to elucidate the pathophysiol. and assists in making therapeutic decisions. Measurement: As well as providing information on regional changes, PET can deliver quant. information about both regional and global changes in metab. This capability of quant. measurement is one of the major advantages of PEt along with physiol. positron tracers, esp. relevant in evaluating diseases which involve the whole myocardium. Discussion: This review discusses major PET tracers for metabolic imaging and their clin. applications and contributions to research regarding ischemic heart disease and other diseases such as heart failure and diabetic heart disease. Future applications of positron metabolic tracers of the detection of vulnerable plaque are also highlighted briefly.
- 201Timmer, S. A. J.; Lubberink, M.; Germans, T.; Götte, M. J. W.; ten Berg, J. M.; ten Cate, F. J.; van Rossum, A. C.; Lammertsma, A. A.; Knaapen, P. Potential of [11C]acetate for measuring myocardial blood flow: Studies in normal subjects and patients with hypertrophic cardiomyopathy. J. Nucl. Cardiol. 2010, 17, 264– 275, DOI: 10.1007/s12350-009-9181-y[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c7ps1Kitg%253D%253D&md5=ed07a56a423db5ceb909e682b520671dPotential of [11C]acetate for measuring myocardial blood flow: Studies in normal subjects and patients with hypertrophic cardiomyopathyTimmer S A J; Lubberink M; Germans T; Gotte M J W; ten Berg J M; ten Cate F J; van Rossum A C; Lammertsma A A; Knaapen PJournal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology (2010), 17 (2), 264-75 ISSN:.BACKGROUND: Measuring the rate of clearance of carbon-11 labelled acetate from myocardium using positron emission tomography (PET) is an accepted technique for noninvasively assessing myocardial oxygen consumption. Initial myocardial uptake of [(11)C]acetate, however, is related to myocardial blood flow (MBF) and several tracer kinetic models for quantifying MBF using [(11)C]acetate have been proposed. The objective of this study was to assess these models. METHODS: Eighteen healthy subjects and 18 patients with hypertrophic cardiomyopathy (HCM) were studied under baseline conditions with [(11)C]acetate and [(15)O]water. Four previously reported methods, including single- and multi-tissue compartment models, were used to calculate MBF from the measured [(11)C]acetate rate of influx K (1) and the (previously) reported relationship between K (1) and MBF. These MBF values were then compared with those derived from corresponding [(15)O]water studies. RESULTS: For all models, correlations between [(11)C]acetate and [(15)O]water-derived MBF ranged from .67 to .86 (all P < .005) in the control group and from .73 to .85 (all P < .001) in the HCM group. Two out of four models systematically underestimated perfusion with [(11)C]acetate, whilst the third model resulted in an overestimation. The fourth model, based on a simple single tissue compartment model with spillover, partial volume and recirculating metabolite corrections, resulted in a regression equation with a slope of near unity and an Y-intercept of almost zero (controls, K(1) = .74[MBF] + .09, r = .86, SEE = .13, P < .001 and HCM, K(1) = .89[MBF] + .03, r = .85, SEE = .12, P < .001). CONCLUSION: [(11)C]acetate enables quantification of MBF in fairly good agreement with actual MBF in both healthy individuals and patients with HCM. A single tissue compartment model with standardized correction for recirculating metabolites and with corrections for partial volume and spillover provided the best results.
- 202Schindler, T. H.; Marashdeh, W.; Solnes, L. Clinical application of myocardial blood flow quantification in CAD patients. Annals of Nuclear Cardiology. 2016, 2, 84– 93, DOI: 10.17996/ANC.02.01.84
- 203Manabe, O.; Naya, M.; Tamaki, N. Feasibility of PET for the management of coronary artery disease: Comparison between CFR and FFR. J. Cardiol. 2017, 70, 135– 140, DOI: 10.1016/j.jjcc.2017.03.002[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czoslCjsQ%253D%253D&md5=966e93a64a977da4aa1da1d49ec259b9Feasibility of PET for the management of coronary artery disease: Comparison between CFR and FFRManabe Osamu; Tamaki Nagara; Naya MasanaoJournal of cardiology (2017), 70 (2), 135-140 ISSN:.Myocardial perfusion imaging using positron emission tomography (PET) allows both qualitative and quantitative measurement. The quantitative myocardial blood flow and coronary flow reserve (CFR) are reliable indices for evaluating functional severity, influenced by both epicardial stenosis and microvascular disease. Fractional flow reserve (FFR) also reflects physiological stenosis, which measures the pressure differences across a coronary artery stenosis during maximum hyperemia. Discordance between CFR and FFR has been noticed in estimating the functional significance of coronary stenosis. In this review, we summarize the feasibility of PET for the management of coronary artery disease compared to FFR.
- 204Stanley, W. C.; Recchia, F. A.; Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 2005, 85, 1093– 1129, DOI: 10.1152/physrev.00006.2004[Crossref], [PubMed], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsFylsr0%253D&md5=90ec99df2f81386d632f74490be7ad04Myocardial substrate metabolism in the normal and failing heartStanley, William C.; Recchia, Fabio A.; Lopaschuk, Gary D.Physiological Reviews (2005), 85 (3), 1093-1129CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review. The alterations in myocardial energy substrate metab. that occur in heart failure, and the causes and consequences of these abnormalities, are poorly understood. There is evidence to suggest that impaired substrate metab. contributes to contractile dysfunction and to the progressive left ventricular remodeling that are characteristic of the heart failure state. The general concept that has recently emerged is that myocardial substrate selection is relatively normal during the early stages of heart failure; however, in the advanced stages there is a downregulation in fatty acid oxidn., increased glycolysis and glucose oxidn., reduced respiratory chain activity, and an impaired reserve for mitochondrial oxidative flux. This review discusses 1) the metabolic changes that occur in chronic heart failure, with emphasis on the mechanisms that regulate the changes in the expression of metabolic genes and the function of metabolic pathways; 2) the consequences of these metabolic changes on cardiac function; 3) the role of changes in myocardial substrate metab. on ventricular remodeling and disease progression; and 4) the therapeutic potential of acute and long-term manipulation of cardiac substrate metab. in heart failure.
- 205Bergmann, S. Imaging of myocardial fatty acid metabolism with PET. Journal of Nuclear Cardiology. 2007, 14, S118– S124, DOI: 10.1016/j.nuclcard.2007.02.007
- 206Bielefeld, D.; Vary, T.; Neely, J. Inhibition of carnitine palmitoyl-CoA transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscle. J. Mol. Cell. Cardiol. 1985, 17, 619– 625, DOI: 10.1016/S0022-2828(85)80030-4[Crossref], [PubMed], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXltVamtLo%253D&md5=1e2e66720da649341a4e22a39e377aedInhibition of carnitine palmitoyl-CoA transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscleBielefeld, David R.; Vary, Thomas C.; Neely, James R.Journal of Molecular and Cellular Cardiology (1985), 17 (6), 619-25CODEN: JMCDAY; ISSN:0022-2828.High concns. of lactate and oxfenicine inhibit fatty acid oxidn. in cardiac muscle. The site of this inhibition was investigated in isolated perfused rat hearts. In hearts perfused with glucose (11 mM) and [U-14C]palmitate (1.0 mM), addn. of 5 mM lactate caused a 38% redn. in 14CO2 prodn. Tissue levels of long-chain acylcarnitine decreased, suggesting that inhibition occurred at either fatty acyl-CoA synthetase or carnitine acyl-CoA transferase. Cytosolic levels of acyl-CoA are low compared with mitochondrial levels and changes in acyl-CoA within the cytosolic compartment cannot be estd. directly. Consequently, the rate of conversion of [14C]palmitate to neutral lipids was used as an indicator of cytosolic acyl-CoA levels. Lactate caused a 100% increase in [14C]fatty acid conversion to triglycerides, suggesting that cytosolic levels of acyl-CoA increased in assocn. with decreased acylcarnitine. Thus, lactate inhibited fatty acid oxidn. at the level of carnitine acyl-CoA transferase. Oxfenicine (2 mM) reduced fatty acid oxidn. by 45%, decreased acylcarnitine levels by 80%, and increased conversion of [14C]palmitate to neutral lipids by 44%, suggesting that oxfenicine also inhibits fatty acid oxidn. at level of carnitine acyl-CoA transferase. Apparently, carnitine acyl-CoA transferase is an important site of control in the pathway of fatty acid oxidn.
- 207Bartels, G. L.; Remme, W. J.; Scholte, H. R. Acute myocardial ischaemia induces cardiac carnitine release in man. Eur. Heart J. 1997, 18, 84– 90, DOI: 10.1093/oxfordjournals.eurheartj.a015122[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3gtF2rtA%253D%253D&md5=59a2163193838ed91230f7d1df3f94deAcute myocardial ischaemia induces cardiac carnitine release in manBartels G L; Remme W J; Scholte H REuropean heart journal (1997), 18 (1), 84-90 ISSN:0195-668X.In animal studies, prolonged periods of ischaemia decrease the cardiac carnitine content. However, whether in humans the heart loses carnitine during short-term ischaemia, and whether this is related to ischaemia-induced cardiac dysfunction, is as yet unknown. Carnitine kinetics were investigated in 28 normotensive patients with significant left coronary artery disease, during and after incremental atrial pacing. To evaluate carnitine kinetics from the ischaemic area, patients were grouped as those with (n = 22) or without (n = 6) myocardial lactate production. Atrial pacing resulted in a comparable maximal heart rate and ST depression in both groups. Carnitine kinetics did not change in those without lactate production. In contrast, coronary venous free carnitine levels increased significantly by 9% during pacing in those with lactate production. Cardiac free carnitine balance changed from uptake (255 +/- 107 pmol.min-1, mean +/- SEM) to release, (-150 +/- 66 pmol.min-1) at 30 min after pacing in the group with lactate production. Arterial and coronary venous differences in free carnitine were significantly correlated with myocardial lactate extraction immediately after pacing. The change in coronary venous free carnitine was significantly correlated with the change in left ventricular ejection fraction at 10 min after pacing. Thus, in patients with coronary artery disease, short-term mild myocardial ischaemia results in significant cardiac free carnitine loss.
- 208Schön, H. R.; Schelbert, H. R.; Robinson, G.; Najafi, A.; Huang, S.-C.; Hansen, H.; Barrio, J.; Kuhl, D. E.; Phelps, M. E. C-11 labeled palmitic acid for the noninvasive evaluation of regional myocardial fatty acid metabolism with positron-computed tomography. Am. Heart J. 1982, 103, 532– 547, DOI: 10.1016/0002-8703(82)90341-6[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL387ls1yluw%253D%253D&md5=0726cccf15ea87ec87526641d9ca0090C- 11 labeled palmitic acid for the noninvasive evaluation of regional myocardial fatty acid metabolism with positron-computed tomography. I. Kinetics of C- 11 palmitic acid in normal myocardiumSchon H R; Schelbert H R; Robinson G; Najafi A; Huang S C; Hansen H; Barrio J; Kuhl D E; Phelps M EAmerican heart journal (1982), 103 (4 Pt 1), 532-47 ISSN:0002-8703.There is no expanded citation for this reference.
- 209Angsten, G.; Valind, S.; Takalo, R.; Neu, H.; Meurling, S.; Långström, B. Inhibition of carnitine-acyl transferase I by oxfenicine studied in vivo with [11C]-labeled fatty acids. Nucl. Med. Biol. 2005, 32, 495– 503, DOI: 10.1016/j.nucmedbio.2005.03.003[Crossref], [PubMed], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvVWmur8%253D&md5=568d6d4a9e3a076d2998a6ffa5067856Inhibition of carnitine-acyl transferase I by oxfenicine studied in vivo with [11C]-labeled fatty acidsAngsten, Gertrud; Valind, Sven; Takalo, Reijo; Neu, Henrik; Meurling, Staffan; Langstroem, BengtNuclear Medicine and Biology (2005), 32 (5), 495-503CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)Methods: Anesthetized pigs were studied with [11C]-labeled fatty acids (FAs) with carbon chain length ranging from 8 to 16 carbon atoms, during control conditions and during inhibition of carnitine-palmitoyl transferase I (CPT I) with oxfenicine. The myocardial uptake of [11C]-FAs from blood was measured together with the relative distribution of [11C]-acyl-CoA between rapid mitochondrial oxidn. and incorporation into slow turnover lipid pools in the heart. Results: During baseline conditions, the fractional oxidative utilization of palmitate was almost as high as that of carnitine-independent short-chain FAs, unless the carnitine shuttle was inhibited by high levels of lactate. Inhibition of CPT I almost completely blocked the oxidative pathway for palmitic acid and reduced the fractional oxidative utilization, while the rate of oxidative metab. of acyl-CoA was unaffected. Conclusions: [11C]-Labeled FAs allow rapid oxidn. to be well sepd. from esterification into slow turnover lipid pools in the heart of anesthetized pigs. The fractional oxidative utilization of [11C]-palmitate serves well to characterize, in vivo, the carnitine-dependent transfer of long-chain FAs.
- 210Ter-Pogossian, M. M.; Klein, M. S.; Markham, J.; Roberts, R.; Sobel, B. E. Regional assessment of myocardial metabolic integrity in vivo by positron-emission tomography with 11C-labeled palmitate. Circulation 1980, 61, 242– 255, DOI: 10.1161/01.CIR.61.2.242[Crossref], [PubMed], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3c%252FptVemtg%253D%253D&md5=1db69371daca17cc08c9aa7f9b49b294Regional assessment of myocardial metabolic integrity in vivo by positron-emission tomography with 11C-labeled palmitateTer-Pogossian M M; Klein M S; Markham J; Roberts R; Sobel B ECirculation (1980), 61 (2), 242-55 ISSN:0009-7322.There is no expanded citation for this reference.
- 211Geltman, E. M. Metabolic imaging of patients with cardiomyopathy. Circulation 1991, 84 (Suppl. 3), I265– 272
- 212Aikawa, T.; Naya, M.; Manabe, O.; Obara, M.; Matsushima, S.; Tamaki, N.; Tsutsui, H. Incidental focal myocardial (18)F-FDG uptake indicating asymptomatic coronary artery disease. J. Nucl. Cardiol. 2016, 23, 596– 598, DOI: 10.1007/s12350-015-0258-5[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC287itlymtg%253D%253D&md5=4f26d1393807e36d7fba6b00fe669ad4Incidental focal myocardial (18)F-FDG uptake indicating asymptomatic coronary artery diseaseAikawa Tadao; Naya Masanao; Obara Masahiko; Matsushima Shouji; Tsutsui Hiroyuki; Manabe Osamu; Tamaki NagaraJournal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology (2016), 23 (3), 596-8 ISSN:.There is no expanded citation for this reference.
- 213Ohira, H.; deKemp, R.; Pena, E.; Davies, R. A.; Stewart, D. J.; Chandy, G.; Contreras-Dominguez, V.; Dennie, C.; Mc Ardle, B.; Mc Klein, R.; Renaud, J. M.; DaSilva, J. N.; Pugliese, C.; Dunne, R.; Beanlands, R.; Mielniczuk, L. M. Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: A potential mechanism for a maladaptive right ventricular response. Eur. Heart J. Cardiovasc Imaging. 2016, 17, 1424– 1431, DOI: 10.1093/ehjci/jev136[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbitVCitg%253D%253D&md5=9d46972e97b143ab13890f6eee35b274Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: a potential mechanism for a maladaptive right ventricular responseOhira Hiroshi; deKemp Robert; Davies Ross A; Stewart Duncan J; Mc Ardle Brian; Mc Klein Ran; Renaud Jennifer M; DaSilva Jean N; Pugliese Carolyn; Dunne Rosemary; Beanlands Rob; Mielniczuk Lisa M; Pena Elena; Dennie Carole; Beanlands Rob; Pena Elena; Stewart Duncan J; Chandy George; Contreras-Dominguez Vladimir; Dennie Carole; Chandy George; Contreras-Dominguez VladimirEuropean heart journal cardiovascular Imaging (2016), 17 (12), 1424-1431 ISSN:.AIMS: We investigated the role of metabolic alterations in the development of a maladaptive right ventricular (RV) response in pulmonary arterial hypertension (PAH), which has not previously been undertaken. This study evaluated relationships between glucose and fatty acid metabolism obtained using PET with invasive pulmonary haemodynamics, RV measurements, and RV function to gain insight into the mechanism of RV maladaptation. METHODS AND RESULTS: Seventeen consecutive PAH patients (mean age 56 ± 15) who underwent right heart catheterization [mean pulmonary arterial pressure (mPAP) 43 ± 12 mmHg] had cardiac 18F-fluoro-2-deoxyglucose (FDG) and (18)F-fluoro-6-thioheptadecanoic acid (FTHA) PET imaging. RV and left ventricular (LV) FDG and FTHA uptake standard uptake values (SUVs) were measured. The SUV was corrected for the partial volume effect (SUVPVE) based on cardiac magnetic resonance imaging (CMR). Right ventricular ejection fraction (RVEF) was determined by CMR. There was a significant positive correlation between mPAP and RV/LV FDG SUVPVE (r = 0.68, P = 0.003), and the ratio of RV/LV FDG SUV : RV/LV FTHA SUV (r = 0.60, P = 0.02). RVEF was negatively correlated with RV/LV FDG SUVPVE uptake (r = -0.56, P = 0.02) and RV/LV FTHA SUVPVE (r = -0.62, P = 0.019). CONCLUSION: Increased pulmonary arterial pressures are associated with increases in the ratio of FDG/FTHA uptake in the RV. Inverse correlation between the uptake of the metabolic tracers and RV function may reflect a shift towards increased fatty acid oxidation and glycolysis associated with RV failure in maladaptive remodelling.
- 214SchÄfers, M.; Riemann, B.; Levkau, B.; Wichter, T.; SchÄfers, K.; Kopka, K.; Breithardt, G.; Schober, O. Current status and future applications of cardiac receptor imaging with positron emission tomography. Nucl. Med. Commun. 2002, 23, 113– 115, DOI: 10.1097/00006231-200202000-00001[Crossref], [PubMed], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD387lvVWksA%253D%253D&md5=5137405266aa61eb7aed3d02a50d5a26Current status and future applications of cardiac receptor imaging with positron emission tomographySchafers M; Riemann B; Levkau B; Wichter T; Schafers K; Kopka K; Breithardt G; Schober ONuclear medicine communications (2002), 23 (2), 113-5 ISSN:0143-3636.There is no expanded citation for this reference.
- 215Lautamäki, R.; Tipre, D.; Bengel, F. M. Cardiac sympathetic neuronal imaging using PET. Eur. J. Nucl. Med. Mol. Imaging 2007, 34 (S1), 74– 85, DOI: 10.1007/s00259-007-0442-1[Crossref], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVaqt7s%253D&md5=8560ffe14bd74bfcf8f03d00d66e1eeeCardiac sympathetic neuronal imaging using PETLautamaki, Riikka; Tipre, Dnyanesh; Bengel, Frank M.European Journal of Nuclear Medicine and Molecular Imaging (2007), 34 (Suppl. 1), S74-S85CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. Introduction Balance of the autonomic nervous system is essential for adequate cardiac performance, and alterations seem to play a key role in the development and progression of various cardiac diseases. PET as an imaging tool PET imaging of the cardiac autonomic nervous system has advanced extensively in recent years, and multiple pre- and postsynaptic tracers have been introduced. The high spatial and temporal resoln. of PET enables noninvasive quantification of neurophysiol. processes at the tissue level. Ligands for catecholamine receptors, along with radiolabeled catecholamines and catecholamine analogs, have been applied to det. involvement of sympathetic dysinnervation at different stages of heart diseases such as ischemia, heart failure, and arrhythmia. Review This review summarizes the recent findings in neurocardiol. PET imaging. Exptl. studies with several radioligands and clin. findings in cardiac dysautonomias are discussed.
- 216Delforge, J.; Syrota, A.; Lançon, J. P.; Nakajima, K.; Loc’h, C.; Janier, M.; Vallois, J. M.; Cayla, J.; Crouzel, C. Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical method. J. Nucl. Med. 1991, 32, 739– 748[PubMed], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlsFSlur8%253D&md5=fad620a42f6f71f921a9f68e0fe0ea03Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical methodDelforge, Jacques; Syrota, Andre; Lancon, Jean Pierre; Nakajima, Kenichi; Loc'h, Christian; Janier, Marc; Vallois, Jean Marie; Cayla, Jerome; Crouzel, ChristianJournal of Nuclear Medicine (1991), 32 (4), 739-48CODEN: JNMEAQ; ISSN:0161-5505.The in vivo quantification of myocardial β-adrenergic receptors was obtained in dogs using positron emission tomog. (PET). The ligand was racemic (±)[11C]CGP-12177, a very potent hydrophilic antagonist of the β-adrenergic receptor. A kinetic method was unsuitable because of the presence of metabolites which made the input function difficult to measure. A graphical method was proposed. The animals were injected with a trace amt. of (±)[11C]CGP-12177, followed 40 min later by a second injection of radioligand with a low-specific activity. An addnl. injection of an excess of unlabeled CGP-12177 was administered after 90 min and allowed for the estn. of the dissocn. rate const. The main advantage of this approach is that the results are obtained without measuring the input function and without estg. the metabolites. The av. value of B'max was 31 pmol/mL of tissue and the dissocn. const. was 0.014 min-1.
- 217Elsinga, P. H.; van Waarde, A.; Vaalburg, W. Receptor imaging in the thorax with PET. Eur. J. Pharmacol. 2004, 499, 1– 13, DOI: 10.1016/j.ejphar.2004.06.057[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnsFSqtbk%253D&md5=d756fb45cf02a246ae732728690ffa69Receptor imaging in the thorax with PETElsinga, Philip H.; van Waarde, Aren; Vaalburg, WillemEuropean Journal of Pharmacology (2004), 499 (1-2), 1-13CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)This review focuses on positron emission tomog. (PET) imaging of receptors in the sympathetic and the parasympathetic systems of heart and lung and highlights the human applications of PET. For the α-adrenoceptor, only [11C]GB67 (N2-{6-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(methyl)amino]hexyl}-N2-[11C]methyl-2-furamide hydrochloride) has been developed. Its potential for application in patients needs to be assessed. For both the β-adrenergic and the muscarinic systems, potent PET radioligands have been prepd. and evaluated in patients. It has been possible to measure receptor densities quant. in human heart {[11C]MQNB: [11C]methylquinuclidinyl benzilate, [11C]CGP12177: S-(3'-t-butylamino-2'-hydroxypropoxy)-benzimidazol-2-[11C]one and [11C]CGP12388: (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one} and qual. in lung {[11C]VC002: N-[11C]-methyl-piperidin-4-yl-2-cyclohexyl-2-hydroxy-2-phenylacetate and [11C]CGP12177}. Besides these subtype nonselective radioligands, the development of compds. that are selective for one subtype are ongoing and have not found successful application in humans yet.
- 218de Jong, R. M.; Willemsen, A. T. M.; Slart, R. H. J. A.; Blanksma, P. K.; van Waarde, A.; Cornel, J. H.; Vaalburg, W.; van Veldhuisen, D. J.; Elsinga, P. H. Myocardial β-adrenoceptor downregulation in idiopathic dilated cardiomyopathy measured in vivo with PET using the new radioligand (S)-[11C]CGP12388. Eur. J. Nucl. Med. Mol. Imaging 2005, 32, 443– 447, DOI: 10.1007/s00259-004-1701-z[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtV2hs78%253D&md5=b6342e37669e287fa77b91b5440c778cMyocardial β-adrenoceptor downregulation in idiopathic dilated cardiomyopathy measured in vivo with PET using the new radioligand (S)-[11C]CGP12388de Jong, Richard M.; Willemsen, Antoon T. M.; Slart, Riemer H. J. A.; Blanksma, Paul K.; van Waarde, Aren; Cornel, Jan Hein; Vaalburg, Willem; van Veldhuisen, Dirk J.; Elsinga, Philip H.European Journal of Nuclear Medicine and Molecular Imaging (2005), 32 (4), 443-447CODEN: EJNMA6; ISSN:1619-7070. (Springer GmbH)The β-adrenoceptor (β-AR) plays an important role in heart failure. Recently, the new tracer (S)-[11C]CGP12388 has been developed. It displays excellent properties for investigation of the cardiac β-ARs in vivo with positron emission tomog. (PET). Furthermore, the simple prodn. method allows its use in a routine clin. setting. The aim of this study was to investigate whether decreased myocardial β-AR d. in patients with idiopathic dilated cardiomyopathy (IDC) can be estd. using (S)-[11C]CGP12388 PET. Myocardial β-AR d. was investigated in six patients with IDC and six age-matched healthy controls, using (S)-[11C]CGP12388 PET. β-AR densities of 5.4±1.3 pmol/g (mean ± SD) were obsd. in patients; these values were significantly lower than those obsd. in healthy controls (8.4±1.5 pmol/g, p<0.005). This study indicates that PET with (S)-[11C]CGP12388 is applicable for the measurement of myocardial β-AR d. in patients. A highly significant redn. in β-AR d. was found in patients with IDC compared with healthy controls.
- 219Naya, M.; Tsukamoto, T.; Morita, K.; Katoh, C.; Nishijima, K.; Komatsu, H.; Yamada, S.; Kuge, Y.; Tamaki, N.; Tsutsui, H. Myocardial beta-adrenergic receptor density assessed by 11C-CGP12177 PET predicts improvement of cardiac function after carvedilol treatment in patients with idiopathic dilated cardiomyopathy. J. Nucl. Med. 2009, 50, 220– 225, DOI: 10.2967/jnumed.108.056341[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjt1Clsb4%253D&md5=5dc05098be2c8f9b4d18a5ba32c9c0a6Myocardial β-adrenergic receptor density assessed by 11C-CGP12177 PET predicts improvement of cardiac function after carvedilol treatment in patients with idiopathic dilated cardiomyopathyNaya, Masanao; Tsukamoto, Takahiro; Morita, Koichi; Katoh, Chietsugu; Nishijima, Kenichi; Komatsu, Hiroshi; Yamada, Satoshi; Kuge, Yuji; Tamaki, Nagara; Tsutsui, HiroyukiJournal of Nuclear Medicine (2009), 50 (2), 220-225CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)We evaluated whether myocardial β-adrenergic receptor (β-AR) d., as detd. by 11C-CGP12177 PET, could predict improvement of cardiac function by β-blocker carvedilol treatment in patients with idiopathic dilated cardiomyopathy (IDC). Methods: Ten patients with IDC (left ventricular ejection fraction [LVEF] < 45%) were studied. Myocardial β-AR d. was estd. using 11C-CGP12177 PET before treatment with carvedilol. Changes of LVEF in response to dobutamine infusion (ΔLVEF-dobutamine) were also measured by echocardiog. Changes of LVEF (ΔLVEF-carvedilol) were evaluated after 20 mo of carvedilol treatment. Results: Baseline myocardial β-AR d. significantly correlated with ΔLVEF-carvedilol (r = -0.88, P < 0.001). In contrast, ΔLVEF-dobutamine did not correlate with ΔLVEF-carvedilol (P = 0.65). Myocardial β-AR d. was the significant multivariate independent predictor of ΔLVEF-carvedilol (β = -0.88, P < 0.001) among univariate predictors, including functional class (r = 0.76, P < 0.05), plasma norepinephrine (r = 0.85, P < 0.01), LVEF (r = -0.64, P < 0.05), and age as confounding factors. Furthermore, myocardial β-AR d. was significantly correlated with plasma norepinephrine (r = -0.79, P < 0.01) and LVEF (r = 0.70, P < 0.05). Conclusion: Myocardial β-AR d. is more tightly related to improvement of LVEF-carvedilol than is cardiac contractile reserve in patients with IDC. Patients with decreased myocardial β-AR have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may receive greater benefit from being treated by antiadrenergic drugs.
- 220Vallabhajosula, S. Molecular Imaging; Springer: Berlin, Heidelberg, 2009.
- 221Gutterman, D. D.; Morgan, D. A.; Miller, F. J. Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction. Circ. Res. 1992, 71, 960– 969, DOI: 10.1161/01.RES.71.4.960[Crossref], [PubMed], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK38zos1Kmsw%253D%253D&md5=5b8158953c9aeb5f2228d64a04ef4ba0Effect of brief myocardial ischemia on sympathetic coronary vasoconstrictionGutterman D D; Morgan D A; Miller F JCirculation research (1992), 71 (4), 960-9 ISSN:0009-7330.The purpose of the present study was to determine whether sympathetic coronary vasoconstrictor responses are altered after brief ischemia and reperfusion. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, left ventricular pressure, left ventricular dP/dt, anterior myocardial wall thickening, and left circumflex coronary artery (LCX) and left anterior descending coronary artery (LAD) blood flow velocities. Changes in coronary vascular resistance were recorded during intravenous bolus doses of norepinephrine and bilateral electrical stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, electrical stimulation of the stellate ganglia increased coronary vascular resistance in the LAD and LCX beds by 38 +/- 5% and 39 +/- 5%, respectively. After a 15-minute LAD occlusion, repeat electrical stimulation produced increases in coronary resistance of 16 +/- 3% and 45 +/- 8%, respectively (p less than 0.05 for the LAD before versus after the occlusion). The peak increase in coronary vascular resistance to two doses of norepinephrine was unchanged. After a shorter period of myocardial ischemia (7 minutes), similar increase in coronary resistance to stellate stimulation were observed before (27 +/- 4%) and after (26 +/- 6%) myocardial ischemia. The mechanism of this impaired sympathetic coronary vasoconstriction was further tested by examining the responses to bretylium and tyramine. Brief ischemia did not alter the coronary constrictor responses to either bretylium or tyramine, suggesting that mechanisms governing prejunctional release of norepinephrine are intact in the postischemic coronary arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)
- 222Raffel, D. M.; Chen, W.; Sherman, P. S.; Gildersleeve, D. L.; Jung, Y.-W. Dependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter density. J. Nucl. Med. 2006, 47, 1490– 1496[PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVCmtLbF&md5=3f08f8090a5d9660d3ef8308ef3f357bDependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter densityRaffel, David M.; Chen, Wei; Sherman, Phillip S.; Gildersleeve, David L.; Jung, Young-WoonJournal of Nuclear Medicine (2006), 47 (9), 1490-1496CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)The norepinephrine analog 11C-meta-hydroxyephedrine (HED) is used with PET to map the regional distribution of cardiac sympathetic neurons. HED is rapidly transported into sympathetic neurons by the norepinephrine transporter (NET) and stored in vesicles. Although much is known about the neuronal mechanisms of HED uptake and retention, there is little information about the functional relationship between HED retention and cardiac sympathetic nerve d. The goal of this study was to characterize the dependence of HED retention on nerve d. in rats with graded levels of cardiac denervation induced chem. with the neurotoxin 6-hydroxydopamine (6-OHDA). Methods: Thirty male Sprague-Dawley rats were divided into 6 groups, and each group was administered a different dose of 6-OHDA: 0 (controls), 7, 11, 15, 22, and 100 mg/kg i.p. One day after 6-OHDA injection, HED (3.7-8.3 MBq) was injected i.v. into each animal and HED concns. in heart and blood at 30 min after injection were detd. Heart tissues were frozen and later processed by tissue homogenization and differential centrifugation into a membrane prepn. for in vitro measurement of cardiac NET d. A satn. binding assay using 3H-mazindol as the radioligand was used to measure NET d. (max. no. of binding sites [Bmax], fmol/mg protein) for each heart. Results: In control animals, NET Bmax was 388 ± 23 fmol/mg protein and HED heart uptake (HU) at 30 min was 2.89% ± 0.35 %ID/g (%ID/g is percentage injected dose per g tissue). The highest 6-OHDA dose of 100 mg/kg caused severe cardiac denervation, decreasing both NET Bmax and HED HU to 8% of their control values. Comparing values for all doses of 6-OHDA, HED retention had a strong linear correlation with NET d.: HU = 0.0077Bmax - 0.028, r2 = 0.95. Conclusion: HED retention is linearly dependent on NET d. in rat hearts that have been chem. denervated with 6-OHDA, suggesting that HED retention is a good surrogate measure of NET d. in the rat heart. This finding is discussed in relation to clin. observations of the dependence of HED retention on cardiac nerve d. in human subjects using PET.
- 223Fallavollita, J. A.; Luisi, A. J.; Michalek, S. M.; Valverde, A. M.; deKemp, R. A.; Haka, M. S.; Hutson, A. D.; Canty, J. M. Prediction of arrhythmic events with positron emission tomography: PAREPET study design and methods. Contemp. Clin. Trials 2006, 27, 374– 388, DOI: 10.1016/j.cct.2006.03.005[Crossref], [PubMed], [CAS], Google Scholar223Prediction of arrhythmic events with positron emission tomography: PAREPET study design and methodsFallavollita James A; Luisi Andrew J Jr; Michalek Suzanne M; Valverde Arturo M; deKemp Robert A; Haka Michael S; Hutson Alan D; Canty John M JrContemporary clinical trials (2006), 27 (4), 374-88 ISSN:1551-7144.BACKGROUND: In medically-treated patients with ischemic cardiomyopathy, myocardial viability is associated with a worse prognosis than scar. The risk is especially great with hibernating myocardium (chronic regional dysfunction with reduced resting flow), and the excess mortality appears to be due to sudden cardiac death (SCD). Hibernating myocardium also results in sympathetic nerve dysfunction, which has been independently associated with risk of SCD. OBJECTIVES: PAREPET is a prospective, observational cohort study funded by NHLBI. It is designed to determine whether hibernating myocardium and/or inhomogeneity of sympathetic innervation by positron emission tomography imaging identifies patients with ischemic cardiomyopathy who are at high risk for SCD and cardiovascular mortality. METHODS: Patients with documented ischemic cardiomyopathy, an ejection fraction ofhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28zpsVGltA%253D%253D&md5=de20a9f86547e5ac466b7c200023c0ec224Carrió, I. Cardiac neurotransmission imaging. J. Nucl. Med. 2001, 42, 1062– 1076[PubMed], [CAS], Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntVSmsL4%253D&md5=ec884220d7a94bb0154b9745e26d4cb0Cardiac neurotransmission imagingCarrio, IgnasiJournal of Nuclear Medicine (2001), 42 (7), 1062-1076CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review. Cardiac neurotransmission imaging with SPECT and PET allows in vivo assessment of presynaptic reuptake and neurotransmitter storage as well as of regional distribution and activity of postsynaptic receptors. In this way, the biochem. processes that occur during neurotransmission can be investigated in vivo at a micromolar level using radiolabeled neurotransmitters and receptor ligands. SPECT and PET of cardiac neurotransmission characterize myocardial neuronal function in primary cardioneuropathies, in which the heart has no significant structural abnormality, and in secondary cardioneuropathies caused by the metabolic and functional changes that take place in different diseases of the heart. In patients with heart failure, the assessment of sympathetic activity has important prognostic implications and will result in better therapy and outcome. In diabetic patients, scintigraphic techniques allow the detection of autonomic neuropathy in early stages of the disease. In conditions with a risk of sudden death, such as idiopathic ventricular tachycardia and arrhythmogenic right ventricular cardiomyopathy, PET and SPECT reveal altered neuronal function when no other structural abnormality is seen. In patients with ischemic heart disease, heart transplantation, drug-induced cardiotoxicity, and dysautonomias, assessment of neuronal function can help characterize the disease and improve prognostic stratification. Future directions include the development of tracers for new types of receptors, the targeting of second messenger mols., and the early assessment of cardiac neurotransmission in genetically predisposed subjects for prevention and early treatment of heart failure.225Luisi, A. J.; Suzuki, G.; Dekemp, R.; Haka, M. S.; Toorongian, S. A.; Canty, J. M.; Fallavollita, J. A. Regional 11C-hydroxyephedrine retention in hibernating myocardium: Chronic inhomogeneity of sympathetic innervation in the absence of infarction. J. Nucl. Med. 2005, 46, 1368– 1374[PubMed], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVGlsb0%253D&md5=140c0304caad159723b54473a8926f96Regional 11C-hydroxyephedrine retention in hibernating myocardium: chronic inhomogeneity of sympathetic innervation in the absence of infarctionLuisi, Andrew J., Jr.; Suzuki, Gen; de Kemp, Robert; Haka, Michael S.; Toorongian, Steven A.; Canty, John M., Jr.; Fallavollita, James A.Journal of Nuclear Medicine (2005), 46 (8), 1368-1374CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)The authors have previously shown that ex vivo counting of 131I-meta-iodobenzylguanidine can identify regional redns. in sympathetic norepinephrine uptake in pigs with hibernating myocardium. However, nonneuronal uptake limited relative differences between regions and would preclude accurate assessment with conventional imaging. The authors therefore hypothesized that the superior specificity of the positron-emitting isotope 11C-hydroxyephedrine (HED) would facilitate the imaging of regional differences, and they designed this study to det. whether altered uptake of norepinephrine by sympathetic nerves in viable, dysfunctional myocardium can be imaged in vivo and to det. the temporal progression and stability of sympathetic dysinnervation in hibernating myocardium. Pigs (n = 15) were chronically instrumented with a 1.5-mm stenosis of the left anterior descending coronary artery, a procedure that was previously shown to produce viable chronically dysfunctional myocardium with reduced resting flow, or hibernating myocardium, after 3 mo. Physiol. studies and HED PET were performed 1-5 mo later with the animals in the closed-chest sedated state. One animal with a myocardial infarct was analyzed sep. After 3 mo, anterior hypokinesis developed (wall thickening, 32% ± 4% vs. 60% ± 4%, P < 0.001), with redns. in resting flow (subendocardial flow, 0.81 ± 0.11 vs. 1.20 ± 0.18 mL/min/g, P < 0.05) and a crit. redn. in subendocardial flow reserve (subendocardial adenosine flow, 0.53 ± 0.20 vs. 3.96 ± 0.43 mL/min/g, P < 0.001). Extensive defects in HED uptake were found for hibernating myocardium, with regional retention ∼50% lower than that in normally perfused remote myocardium (0.035 ± 0.002 vs. 0.066 ± 0.002 min-1, P < 0.001). Relative HED uptake (left anterior descending coronary artery/remote) was lower in chronically instrumented animals than in control animals (n = 4, P < 0.001) and animals studied 1 mo after instrumentation (n = 2, P < 0.05). The regional redn. in sympathetic nerve function was persistent and unaltered for at least 2 mo after the development of hibernating myocardium. Hibernating myocardium is assocd. with persistent redns. in regional uptake of norepinephrine by sympathetic nerves. The inhomogeneity in sympathetic innervation in viable dysfunctional myocardium is similar to that occurring after myocardial infarction and may contribute to arrhythmic death in patients with ischemic cardiomyopathy.226Raffel, D. M.; Koeppe, R. A.; Jung, Y.-W.; Gu, G.; Jang, K. S.; Sherman, P. S.; Quesada, C. A. Quantification of cardiac sympathetic nerve density with N-11C-guanyl-meta-octopamine and tracer kinetic analysis. J. Nucl. Med. 2013, 54, 1645– 1652, DOI: 10.2967/jnumed.113.120659[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFyntr7I&md5=c68fc3c0b6b45fa45914e4e61bb6c4d0Quantification of cardiac sympathetic nerve density with N-11C-guanyl-meta-octopamine and tracer kinetic analysisRaffel, David M.; Koeppe, Robert A.; Jung, Yong-Woon; Gu, Guie; Jang, Keun Sam; Sherman, Phillip S.; Quesada, Carole A.Journal of Nuclear Medicine (2013), 54 (9), 1645-1652CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)Most cardiac sympathetic nerve radiotracers are substrates of the norepinephrine transporter (NET). Existing tracers such as 123I-metaiodobenzylguanidine (123I-MIBG) and 11C-(-)-meta-hydroxy-ephedrine (11C-HED) are flow-limited tracers because of their rapid NET transport rates. This prevents successful application of kinetic anal. techniques and causes semiquant. measures of tracer retention to be insensitive to mild-to-moderate nerve losses. N-11C-guanyl-(-)-meta-octopamine (11C-GMO) has a much slower NET transport rate and is trapped in storage vesicles. The goal of this study was to det. whether analyses of 11C-GMO kinetics could provide robust and sensitive measures of regional cardiac sympathetic nerve densities. Methods: PET studies were performed in a rhesus macaque monkey under control conditions or after i.v. infusion of the NET inhibitor desipramine (DMI). Five desipramine dose levels were used to establish a range of available cardiac NET levels. Compartmental modeling of 11C-GMO kinetics yielded ests. of the rate consts. K1 (mL/min/g), k2 (min-1), and k3 (min-1). These values were used to calc. a net uptake rate const. Ki (mL/min/g) = (K1k3)/(k2 + k3). In addn., Patlak graphical analyses of 11C-GMO kinetics yielded Patlak slopes Kp (mL/min/g), which represent alternative measurements of the net uptake rate const. Ki. 11C-GMO kinetics in isolated rat hearts were also measured for comparison with other tracers. Results: In isolated rat hearts, the neuronal uptake rate of 11C-GMO was 8 times slower than 11C-HED and 12 times slower than 11C-MIBG. 11C-GMO also had a long neuronal retention time (>200 h). Compartmental modeling of 11C-GMO kinetics in the monkey heart proved stable under all conditions. Calcd. net uptake rate consts. Ki tracked desipramine-induced redns. of available NET in a dose-dependent manner, with a half maximal inhibitory concn. (IC50) of 0.087 ± 0.012 mg of desipramine per kg. Patlak anal. provided highly linear Patlak plots, and the Patlak slopes Kp also declined in a dose-dependent manner (IC50 = 0.068 ± 0.010 mg of desipramine per kg). Conclusion: Compartmental modeling and Patlak anal. of 11C-GMO kinetics each provided quant. parameters that accurately tracked changes in cardiac NET levels. These results strongly suggest that PET studies with 11C-GMO can provide robust and sensitive quant. measures of regional cardiac sympathetic nerve densities in human hearts.227Thackeray, J. T.; Bengel, F. M. PET imaging of the autonomic nervous system. Q. J. Nucl. Med. Mol. Imaging 2016, 60, 362– 382[PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szovVOgtg%253D%253D&md5=d007fcdc6206ae3f8400b8bf1369f786PET imaging of the autonomic nervous systemThackeray James T; Bengel Frank MThe quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.. (2016), 60 (4), 362-82 ISSN:.The autonomic nervous system is the primary extrinsic control of heart rate and contractility, and is subject to adaptive and maladaptive changes in cardiovascular disease. Consequently, noninvasive assessment of neuronal activity and function is an attractive target for molecular imaging. A myriad of targeted radiotracers have been developed over the last 25 years for imaging various components of the sympathetic and parasympathetic signal cascades. While routine clinical use remains somewhat limited, a number of larger scale studies in recent years have supplied momentum to molecular imaging of autonomic signaling. Specifically, the findings of the ADMIRE HF trial directly led to United States Food and Drug Administration approval of 123I-metaiodobenzylguanidine (MIBG) for Single Photon Emission Computed Tomography (SPECT) assessment of sympathetic neuronal innervation, and comparable results have been reported using the analogous PET agent 11C-meta-hydroxyephedrine (HED). Due to the inherent capacity for dynamic quantification and higher spatial resolution, regional analysis may be better served by PET. In addition, preliminary clinical and extensive preclinical experience has provided a broad foundation of cardiovascular applications for PET imaging of the autonomic nervous system. Recent years have witnessed the growth of novel quantification techniques, expansion of multiple tracer studies, and improved understanding of the uptake of different radiotracers, such that the transitional biology of dysfunctional subcellular catecholamine handling can be distinguished from complete denervation. As a result, sympathetic neuronal molecular imaging is poised to play a role in individualized patient care, by stratifying cardiovascular risk, visualizing underlying biology, and guiding and monitoring therapy.228Sinusas, A. J.; Lazewatsky, J.; Brunetti, J.; Heller, G.; Srivastava, A.; Liu, Y.-H.; Sparks, R.; Puretskiy, A.; Lin, S.; Crane, P.; Carson, R. E.; Lee, L. V. Biodistribution and radiation dosimetry of LMI1195: First-in-human study of a novel 18F-labeled tracer for imaging myocardial innervation. J. Nucl. Med. 2014, 55, 1445– 1451, DOI: 10.2967/jnumed.114.140137[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVSrur3M&md5=ba681968cd70fbf95871a76c759dd644Biodistribution and radiation dosimetry of LMI1195: first-in-human study of a Novel 18F-labeled tracer for imaging myocardial innervationSinusas, Albert J.; Lazewatsky, Joel; Brunetti, Jacqueline; Heller, Gary; Srivastava, Ajay; Liu, Yi-Hwa; Sparks, Richard; Puretskiy, Andrey; Lin, Shu-fei; Crane, Paul; Carson, Richard E.; Lee, L. VeronicaJournal of Nuclear Medicine (2014), 55 (9), 1445-1451CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)A novel 18F-labeled ligand for the norepinephrine transporter (N-[3-bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine [LMI1195]) is in clin. development for mapping cardiac nerve terminals in vivo using PET. Human safety, whole-organ biodistribution, and radiation dosimetry of LMI1195 were evaluated in a phase 1 clin. trial. Methods: Twelve healthy subjects at 3 clin. sites were injected i.v. with 150-250 MBq of LMI1195. Dynamic PET images were obtained over the heart for 10 min, followed by sequential whole-body images for approx. 5 h. Blood samples were obtained, and heart rate, ECG, and blood pressure were monitored before and during imaging. Residence times were detd. from multiexponential regression of organ region-of-interest data normalized by administered activity (AA). Radiation dose ests. were calcd. using OLINDA/EXM. Myocardial, lung, liver, and blood-pool standardized uptake values were detd. at different time intervals. Results: No adverse events due to LMI1195 were seen. Blood radioactivity cleared quickly, whereas myocardial uptake remained stable and uniform throughout the heart over 4 h. Liver and lung activity cleared relatively rapidly, providing favorable target-to-background ratios for cardiac imaging. The urinary bladder demonstrated the largest peak uptake (18.3% AA), followed by the liver (15.5% AA). The mean ED was 0.026 ± 0.0012 mSv/MBq. Approx. 1.6% AA was seen in the myocardium initially, remaining above 1.5% AA (decay-cor.) through 4 h after injection. The myocardium-to-liver ratio was approx. unity initially, increasing to more than 2 at 4 h. Conclusion: These preliminary data suggest that LMI1195 is well tolerated and yields a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. The kinetics of myocardial and adjacent organ activity suggest that cardiac imaging should be possible with acceptable patient radiation dose.229Pacher, P.; Steffens, S.; Haskó, G.; Schindler, T. H.; Kunos, G. Cardiovascular effects of marijuana and synthetic cannabinoids: The good, the bad, and the ugly. Nat. Rev. Cardiol. 2018, 15, 151– 166, DOI: 10.1038/nrcardio.2017.130[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2isLnN&md5=9f1ce4c6c3173e5c9c4dc19a307c99d0Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the uglyPacher, Pal; Steffens, Sabine; Hasko, Gyorgy; Schindler, Thomas H.; Kunos, GeorgeNature Reviews Cardiology (2018), 15 (3), 151-166CODEN: NRCAE6; ISSN:1759-5002. (Nature Research)Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ9-tetrahydrocannabinol (THC), is an agonist of both CB1R and CB2R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogs might be the underlying cause of severe cardiovascular events and pathologies.230Valenta, I.; Varga, Z. V.; Valentine, H.; Cinar, R.; Horti, A.; Mathews, W. B.; Dannals, R. F.; Steele, K.; Kunos, G.; Wahl, R. L.; Pomper, M. G.; Wong, D. F.; Pacher, P.; Schindler, T. H. Feasibility evaluation of myocardial cannabinoid type 1 receptor imaging in obesity. JACC: Cardiovascular Imaging. 2018, 11, 320– 332, DOI: 10.1016/j.jcmg.2017.11.019[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mvos1aqtw%253D%253D&md5=0613321cb418452cbb16c8bb38e15207Feasibility Evaluation of Myocardial Cannabinoid Type 1 Receptor Imaging in Obesity: A Translational ApproachValenta Ines; Valentine Heather; Horti Andrew; Mathews William B; Dannals Robert F; Pomper Martin G; Wong Dean F; Varga Zoltan V; Cinar Resat; Kunos George; Steele Kimberley; Wahl Richard L; Pacher Pal; Schindler Thomas HJACC. Cardiovascular imaging (2018), 11 (2 Pt 2), 320-332 ISSN:.OBJECTIVES: The aim of this study was to evaluate the feasibility of targeted imaging of myocardial cannabinoid type 1 receptor (CB1-R) and its potential up-regulation in obese mice with translation to humans using [(11)C]-OMAR and positron emission tomography (PET)/computed tomography (CT). BACKGROUND: Activation of myocardial CB1-R by endocannabinoids has been implicated in cardiac dysfunction in diabetic mice. Obesity may lead to an up-regulation of myocardial CB1-R, potentially providing a mechanistic link between obesity and the initiation and/or progression of cardiomyopathy. METHODS: Binding specificity of [(11)C]-OMAR to CB1-R was investigated by blocking studies with rimonabant in mice. The heart was harvested from each mouse, and its radioactivity was determined by γ-counter. Furthermore, [(11)C]-OMAR dynamic micro-PET/CT was carried out in obese and normal-weight mice. Ex vivo validation was performed by droplet digital polymerase chain reaction (absolute quantification) and RNAscope Technology (an in situ ribonucleic acid analysis platform). Subsequently, myocardial CB1-R expression was probed noninvasively with intravenous injection of CB1-R ligand [(11)C]-OMAR and PET/CT in humans with advanced obesity and normal-weight human control subjects, respectively. RESULTS: Rimonabant significantly blocked OMAR uptake in the heart muscle compared with vehicle, signifying specific binding of OMAR to the CB1-R in the myocardium. The myocardial OMAR retention quantified by micro-PET/CT in mice was significantly higher in obese compared with normal-weight mice. Absolute quantification of CB1-R gene expression with droplet digital polymerase chain reaction and in situ hybridization confirmed CB1-R up-regulation in all major myocardial cell types (e.g., cardiomyocytes, endothelium, vascular smooth muscle cells, and fibroblasts) of obese mice. Obese mice also had elevated myocardial levels of endocannabinoids anandamide and 2-arachidonoylglycerol compared with lean mice. Translation to humans revealed higher myocardial OMAR retention in advanced obesity compared with normal-weight subjects. CONCLUSIONS: Noninvasive imaging of cardiac CB1-R expression in obesity is feasible applying [(11)C]-OMAR and PET/CT. These results may provide a rationale for further clinical testing of CB1-R-targeted molecular imaging in cardiometabolic diseases.231Fukushima, K.; Bravo, P. E.; Higuchi, T.; Schuleri, K. H.; Lin, X.; Abraham, M. R.; Xia, J.; Mathews, W. B.; Dannals, R. F.; Lardo, A. C.; Szabo, Z.; Bengel, F. M. Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin II type 1 receptors. J. Am. Coll. Cardiol. 2012, 60, 2527– 2534, DOI: 10.1016/j.jacc.2012.09.023[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCrs7fL&md5=3f7730bcb9d5ba6e92d2a90c7c392f3aMolecular Hybrid Positron Emission Tomography/Computed Tomography Imaging of Cardiac Angiotensin II Type 1 ReceptorsFukushima, Kenji; Bravo, Paco E.; Higuchi, Takahiro; Schuleri, Karl H.; Lin, Xiaoping; Abraham, M. Roselle; Xia, Jinsong; Mathews, William B.; Dannals, Robert F.; Lardo, Albert C.; Szabo, Zsolt; Bengel, Frank M.Journal of the American College of Cardiology (2012), 60 (24), 2527-2534CODEN: JACCDI; ISSN:0735-1097. (Elsevier Inc.)The goal of this study was to explore the feasibility of targeted imaging of the angiotensin II type 1 receptor (AT1R) in cardiac tissue, using clin. hybrid positron emission tomog./computed tomog. (PET/CT). AT1R is an attractive imaging target due to its key role in various cardiac pathologies, including post-infarct left ventricular remodeling. Using the novel AT1R ligand [11C]-KR31173, dynamic PET/CT was performed in young farm pigs under healthy conditions (n = 4) and 3 to 4 wk after exptl. myocardial infarction (n = 5). Ex vivo validation was carried out by immunohistochem. and polymerase chain reaction. First-in-man application was performed in 4 healthy volunteers at baseline and under AT1R blocking. In healthy pigs, myocardial KR31173 retention was detectable, regionally homogeneous, and specific for AT1R, as confirmed by blocking expts. Metab. in plasma was low (85 ± 2% of intact tracer after 60 min). After myocardial infarction, KR31173 retention, cor. for regional perfusion, revealed AT1R up-regulation in the infarct area relative to remote myocardium, whereas retention was elevated in both regions when compared with myocardium of healthy controls (8.7 ± 0.8% and 7.1 ± 0.3%/min vs. 5.8 ± 0.4%/min for infarct and remote, resp., vs. healthy controls; p < 0.01 each). Postmortem anal. confirmed AT1R up-regulation in remote and infarct tissue. First-in-man application was safe, and showed detectable and specific myocardial KR31173 retention, albeit at a lower level than pigs (left ventricular av. retention: 1.2 ± 0.1%/min vs. 4.4 ± 1.2%/min for humans vs. pigs; p = 0.04). Noninvasive imaging of cardiac AT1R expression is feasible using clin. PET/CT technol. Results provide a rationale for broader clin. testing of AT1R-targeted mol. imaging.232Schindler, T. H.; Dilsizian, V. Cardiac positron emission tomography/computed tomography imaging of the renin-angiotensin system in humans holds promise for image-guided approach to heart failure therapy. J. Am. Coll. Cardiol. 2012, 60, 2535– 2538, DOI: 10.1016/j.jacc.2012.09.022[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s7ktVegtA%253D%253D&md5=2f2c4f977b2acf5c1672ebfa90210e30Cardiac positron emission tomography/computed tomography imaging of the Renin-Angiotensin system in humans holds promise for image-guided approach to heart failure therapySchindler Thomas H; Dilsizian VaskenJournal of the American College of Cardiology (2012), 60 (24), 2535-8 ISSN:.There is no expanded citation for this reference.233Higuchi, T.; Fukushima, K.; Xia, J.; Mathews, W. B.; Lautamaki, R.; Bravo, P. E.; Javadi, M. S.; Dannals, R. F.; Szabo, Z.; Bengel, F. M. Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury. J. Nucl. Med. 2010, 51, 1956– 1961, DOI: 10.2967/jnumed.110.079855[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbos1ynsg%253D%253D&md5=a8b65e27ea573fc2012f44310372b52fRadionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injuryHiguchi Takahiro; Fukushima Kenji; Xia Jinsong; Mathews William B; Lautamaki Riikka; Bravo Paco E; Javadi Mehrbod S; Dannals Robert F; Szabo Zsolt; Bengel Frank MJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2010), 51 (12), 1956-61 ISSN:.UNLABELLED: The renin-angiotensin system (RAS) mediates proapoptotic, profibrotic, and proinflammatory processes in maladaptive conditions. Activation after myocardial infarction may initialize and promote cardiac remodeling. Using a novel positron-emitting ligand, we sought to determine the presence and time course of regional myocardial upregulation of the angiotensin II type 1 receptor (AT1R) and the blocking efficacy of various anti-RAS agents. METHODS: In male Wistar rats (n = 31), ischemia-reperfusion damage was induced by 20- to 25-min ligation of the left coronary artery. The AT1R blocker (11)C-2-butyl-5-methoxymethyl-6-(1-oxopyridin-2-yl)-3-[[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine ((11)C-KR31173) was injected intravenously at different times until 6 mo after surgery and sacrifice. Autoradiography, histology, and immunohistochemistry were performed for ex vivo validation. Additional in vivo PET was conducted in 3 animals. A second series of experiments (n = 16) compared untreated animals with animals treated with oral valsartan (50 mg/kg/d), oral enalapril (10 mg/kg/d), and complete intravenous blockage (SK-1080, 2 mg/kg, 10 min before imaging). RESULTS: Transient regional AT1R upregulation was detected in the infarct area, with a peak at 1-3 wk after surgery (autoradiographic infarct-to-remote ratio, 1.07 ± 0.09, 1.68 ± 0.34, 2.54 ± 0.40, 2.98 ± 0.70, 3.16 ± 0.57, 1.86 ± 0.65, and 1.28 ± 0.27 at control, day 1, day 3, week 1, week 3, month 3, and month 6, respectively). The elevated uptake of (11)C-KR31173 in the infarct area was detectable by small-animal PET in vivo, and it was blocked completely by intravenous SK-1080. Although oral treatment with enalapril did not reduce focal tracer uptake, oral valsartan resulted in partial blockade (infarct-to-remote ratio, 2.94 ± 0.52, 2.88 ± 0.60, 2.07 ± 0.25, and 1.26 ± 0.10 for no treatment, enalapril, valsartan, and SK-1080, respectively). CONCLUSION: After ischemic myocardial damage in a rat model, transient regional AT1R upregulation is detectable in the infarct area using (11)C-KR31173. Inhibitory effects of the clinical AT1R blocker valsartan can be identified, whereas blockage of upstream angiotensin-converting enzyme with enalapril does not affect AT1R density. These results provide a rationale for subsequent testing of AT1R-targeted imaging to predict the risk for ventricular remodeling and to monitor the efficacy of anti-RAS drug therapy.234Quercioli, A.; Montecucco, F.; Pataky, Z.; Thomas, A.; Ambrosio, G.; Staub, C.; Di Marzo, V.; Ratib, O.; Mach, F.; Golay, A.; Schindler, T. H. Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokines. Eur. Heart J. 2013, 34, 2063– 2073, DOI: 10.1093/eurheartj/eht085[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svlsFaqsg%253D%253D&md5=8e9a6284cbf573f2e1b086e0129d0ed6Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokinesQuercioli Alessandra; Montecucco Fabrizio; Pataky Zoltan; Thomas Aurelien; Ambrosio Giuseppe; Staub Christian; Di Marzo Vincenzo; Ratib Osman; Mach Francois; Golay Alain; Schindler Thomas HEuropean heart journal (2013), 34 (27), 2063-73 ISSN:.AIMS: To investigate the effect of surgical gastric bypass-induced weight loss and related alterations in endocannabinoids (ECs) and adipocytokine plasma levels on coronary circulatory dysfunction in morbidly obese (MOB) individuals. METHODS AND RESULTS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) from rest (ΔMBF) and during pharmacologically induced hyperaemia were measured with 13N-ammonia PET/CT in 18 MOB individuals with a body mass index (BMI) > 40 kg/m2 at baseline and after a median follow-up period of 22 months. Gastric bypass intervention decreased BMI from a median of 44.8 (inter-quartile range: 43.3, 48.2) to 30.8 (27.3, 34.7) kg/m2 (P < 0.0001). This decrease in BMI was accompanied by a marked improvement in endothelium-related ΔMBF to CPT and hyperaemic MBFs, respectively [0.34 (0.18, 0.41) from 0.03 (-0.08, 0.15) mL/g/min, P = 0.002; and 2.51 (2.17, 2.64) from 1.53 (1.39, 2.18) mL/g/min, P < 0.001]. There was an inverse correlation between decreases in plasma concentrations of the EC anandamide and improvement in ΔMBF to CPT (r = -0.59, P = 0.009), while increases in adiponectin plasma levels correlated positively with hyperaemic MBFs (r = 0.60, P = 0.050). Conversely, decreases in leptin plasma concentrations were not observed to correlate with the improvement in coronary circulatory function (r = 0.22, P = 0.400, and r = -0.31, P = 0.250). CONCLUSIONS: Gastric bypass-related reduction of BMI in MOB individuals beneficially affects coronary circulatory dysfunction. The dysbalance between ECs and adipocytokines appears to be an important determinant of coronary circulatory function in obesity.235Quercioli, A.; Pataky, Z.; Vincenti, G.; Makoundou, V.; Di Marzo, V.; Montecucco, F.; Carballo, S.; Thomas, A.; Staub, C.; Steffens, S.; Seimbille, Y.; Golay, A.; Ratib, O.; Harsch, E.; Mach, F.; Schindler, T. H. Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur. Heart J. 2011, 32, 1369– 1378, DOI: 10.1093/eurheartj/ehr029[Crossref], [PubMed], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntF2ht7Y%253D&md5=b3fa1b171901fb082f23aff18ffbeed5Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesityQuercioli, Alessandra; Pataky, Zoltan; Vincenti, Gabriella; Makoundou, Vincent; Di Marzo, Vincenzo; Montecucco, Fabrizio; Carballo, Sebastian; Thomas, Aurelien; Staub, Christian; Steffens, Sabine; Seimbille, Yann; Golay, Alain; Ratib, Osman; Harsch, Elisabetta; Mach, Francois; Schindler, Thomas H.European Heart Journal (2011), 32 (11), 1369-1378CODEN: EHJODF; ISSN:0195-668X. (Oxford University Press)Aims: Aim of this study was to evaluate a possible assocn. between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. Methods and results: Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacol. vasodilation with dipyridamole were measured with 13N-ammonia PET/CT. Study participants (n = 77) were divided into three groups based on their body mass index (BMI, kg/m2): control group 20≤ BMI <25 (n = 21); overweight group, 25≤ BMI <30 (n = 26); and obese group, BMI ≥30 (n = 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, resp. 0.68 (0.53, 0.78) vs. 0.56 0.47, 0.66 ng/mL, P = 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P = 0.806. The endothelium-related change in MBF during CPT from rest (ΔMBF) progressively declined in overweight and obese when compared with control group 0.21 (0.10, 0.27) and 0.09 (-0.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P = 0.010 and P = 0.0001, resp. Compared with controls, hyperemic MBFs were significantly lower in overweight and obese individuals 2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P = 0.007 and P = 0.042, resp. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with ΔMBF to CPT (r = -0.37, P = 0.046 and r = -0.48, P = 0.008) and hyperemic MBFs (r = -0.38, P = 0.052 and r = -0.45, P = 0.017), resp. Conclusions: Increased EC plasma levels of AEA and 2-AG are assocd. with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.236Pacher, P.; Kunos, G. Modulating the endocannabinoid system in human health and disease - successes and failures. FEBS J. 2013, 280, 1918– 1943, DOI: 10.1111/febs.12260[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmsFWgu7w%253D&md5=831af5bc7f9fc21acab7c517e58c7e74Modulating the endocannabinoid system in human health and disease - successes and failuresPacher, Pal; Kunos, GeorgeFEBS Journal (2013), 280 (9), 1918-1943CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)A review. The discovery of the endocannabinoid system, comprising the G-protein coupled cannabinoid 1 and 2 receptors (CB1/2), their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, has triggered an avalanche of exptl. studies implicating the endocannabinoid system in a growing no. of physiol./pathol. functions. These studies have also suggested that modulating the activity of the endocannabinoid system holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders; obesity/metabolic syndrome; cachexia; chemotherapy-induced nausea and vomiting; and tissue injury and pain, amongst others. However, clin. trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally-restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain, have introduced unexpected complexities, suggesting that a better understanding of the pathophysiol. role of the endocannabinoid system is required to devise clin. successful treatment strategies.237Rajesh, M.; Batkai, S.; Kechrid, M.; Mukhopadhyay, P.; Lee, W.-S.; Horvath, B.; Holovac, E.; Cinar, R.; Liaudet, L.; Mackie, K.; Hasko, G.; Pacher, P. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes 2012, 61, 716– 727, DOI: 10.2337/db11-0477[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XovFegurk%253D&md5=3eb168ce66bcbc292cf8e267497ff87fCannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathyRajesh, Mohanraj; Batkai, Sandor; Kechrid, Malek; Mukhopadhyay, Partha; Lee, Wen-Shin; Horvath, Bela; Holovac, Eileen; Cinar, Resat; Liaudet, Lucas; Mackie, Ken; Hasko, Gyorgy; Pacher, PalDiabetes (2012), 61 (3), 716-727CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)Endocannabinoids and cannabinoid 1 (CB1) receptors have been implicated in cardiac dysfunction, inflammation, and cell death assocd. with various forms of shock, heart failure, and atherosclerosis, in addn. to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB1 receptors in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH2-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion mol. 1, and vascular cell adhesion mol. 1), increased expression of CB1, advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT1R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isoenzyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). Pharmacol. inhibition or genetic deletion of CB1 receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathol. alterations. Activation of CB1 receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT1R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB1 receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.238Lim, S. L.; Lam, C. S. P.; Segers, V. F. M.; Brutsaert, D. L.; De Keulenaer, G. W. Cardiac endothelium–myocyte interaction: Clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur. Heart J. 2015, 36, 2050– 2060, DOI: 10.1093/eurheartj/ehv132[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFertrnF&md5=ae37c68fe6133b7f8c91527e8427ba64Cardiac endothelium-myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fractionLim, Shir Lynn; Lam, Carolyn S. P.; Segers, Vincent F. M.; Brutsaert, Dirk L.; De Keulenaer, Gilles W.European Heart Journal (2015), 36 (31), 2050-2060,2060b,2060c,2060dCODEN: EHJODF; ISSN:0195-668X. (Oxford University Press)Heart failure (HF) is an important global health problem with great socioeconomic burden. Outcomes remain sub-optimal. Endothelium-cardiomyocyte interactions play essential roles in cardiovascular homeostasis, and deranged endothelium-related signalling pathways have been implicated in the pathophysiol. of HF. In particular, disturbances in nitric oxide (NO)-mediated pathway and neuregulin-mediated pathway have been shown to contribute to the development of HF. These signalling pathways hold the potential as pathophysiol. targets for new HF therapies, and may aid in patient selection for future HF trials.239Paulus, W. J.; Tschöpe, C. A novel paradigm for heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 2013, 62, 263– 271, DOI: 10.1016/j.jacc.2013.02.092[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3snkslehtQ%253D%253D&md5=487286e6a7480237a3f14a783efb3476A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammationPaulus Walter J; Tschope CarstenJournal of the American College of Cardiology (2013), 62 (4), 263-71 ISSN:.Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.240Fish, K. M.; Hajjar, R. J. Myocardial cannabinoid receptor imaging in obesity. JACC: Cardiovascular Imaging. 2018, 11, 333– 335, DOI: 10.1016/j.jcmg.2017.12.001[Crossref], [PubMed], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mvos1aqtA%253D%253D&md5=9db693742957a67c8ed8099e3370938eMyocardial Cannabinoid Receptor Imaging in ObesityFish Kenneth M; Hajjar Roger JJACC. Cardiovascular imaging (2018), 11 (2 Pt 2), 333-335 ISSN:.There is no expanded citation for this reference.241White, F. J.; Kalivas, P. W. Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend. 1998, 51, 141– 153, DOI: 10.1016/S0376-8716(98)00072-6[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXks1Olsbo%253D&md5=46663898a8b5b199218728fb800028c6Neuroadaptations involved in amphetamine and cocaine addictionWhite, Francis J.; Kalivas, Peter W.Drug and Alcohol Dependence (1998), 51 (1,2), 141-153CODEN: DADEDV; ISSN:0376-8716. (Elsevier Science Ireland Ltd.)A review with 149 refs., describing mol. interactions of cocaine and amphetamine with dopamine transporters, acute effects of psychostimulants, repeated administration of psychostimulants, and neuroadaptation in glutamate transmission.242Fowler, J. S.; Volkow, N. D.; Wolf, A. P.; Dewey, S. L.; Schlyer, D. J.; MacGregor, R. R.; Hitzemann, R.; Logan, J.; Bendriem, B.; Gatley, S. J.; Christman, D. Mapping cocaine binding sites in human and baboon brain in vivo. Synapse 1989, 4, 371– 377, DOI: 10.1002/syn.890040412[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXptFKhtw%253D%253D&md5=b5adb05a934b154e8fd7511579eaca84Mapping cocaine binding sites in human and baboon brain in vivoFowler, Joanna S.; Volkow, Nora D.; Wolf, Alfred P.; Dewey, Stephen L.; Schlyer, David J.; Macgregor, Robert R.; Hitzemann, Robert; Logan, Jean; Bendriem, Bernard; et al.Synapse (New York, NY, United States) (1989), 4 (4), 371-7CODEN: SYNAET; ISSN:0887-4476.The direct measurements of cocaine binding in human and baboon brain were made by using positron tomog. (PET) and tracer doses of [N-11C-methyl]-(-)-cocaine ([11C]cocaine). Cocaine's binding and release from brain were rapid with the highest regional uptake of 11C occurring in the corpus striatum at 4-10 min after i.v. injection of labeled cocaine. This was followed by a clearance to half the peak value at 25 min with the overall time course paralleling the peak behavioral activation and subsequent decline after i.v. cocaine administration. Blockade of the dopamine reuptake sites with nomifensine reduced the striatal but not the cerebellar uptake of [11C]cocaine in baboons indicating that cocaine binding is assocd. with the dopamine reuptake site in the corpus striatum. While cocaine is rapidly metabolized in both human and baboon, the profile of labeled metabolites is different, with baboon plasma contg. significant amts. of labeled CO2 but not human plasma. These data showed the feasibility of using [11C]cocaine and PET to map binding sites for cocaine in human brain, to study its kinetics and binding mechanism.243Wang, G.-J.; Volkow, N. D.; Fowler, J. S.; Fischman, M.; Foltin, R.; Abumrad, N. N.; Logan, J.; Pappas, N. R. Cocaine abusers do not show loss of dopamine transporters with age. Life Sci. 1997, 61, 1059– 1065, DOI: 10.1016/S0024-3205(97)00614-0[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlsVCkt7g%253D&md5=e55b0005fee05a19f9293d54d490a7feCocaine abusers do not show loss of dopamine transporters with ageWang, Gene-Jack; Volkow, Nora D.; Fowler, Joanna S.; Fischman, Marian; Foltin, Richard; Abumrad, Naji N.; Logan, Jean; Pappas, Naomi R.Life Sciences (1997), 61 (11), 1059-1065CODEN: LIFSAK; ISSN:0024-3205. (Elsevier)Cocaine blocks dopamine transporters (DAT) and this effect is crucial to its reinforcing properties. To assess the effects of chronic cocaine on DAT we evaluated 20 current cocaine abusers and 20 age matched controls using PET and [C-11]cocaine as a DAT ligand. Though there were no differences in DAT availability between groups, current cocaine abusers (and 12 detoxified cocaine abusers studied previously) did not show the typical age-related decline in DAT seen in controls. Though further studies are required to rule out sampling effects and to control for confounding variables (i.e. smoking), one could speculate that chronic DAT blockade by cocaine has a protective effect on the loss of DAT with age.244Volkow, N. Cocaine uptake is decreased in the brain of detoxified cocaine abusers. Neuropsychopharmacology 1996, 14, 159– 168, DOI: 10.1016/0893-133X(95)00073-M[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XitVGrtbo%253D&md5=b12ff4f1c8122b03f41157e883f849faCocaine uptake is decreased in the brain of detoxified cocaine abusersVolkow, N. D.; Wang, G. -J.; Fowler, J. S.; Logan, J.; Hitzemann, R.; Gatley, S. J.; MacGregor, R. R.; Wolf, A. P.Neuropsychopharmacology (1996), 14 (3), 159-68CODEN: NEROEW; ISSN:0893-133X. (Elsevier)Binding of [11C]cocaine in brain was measured with positron emission tomog. in 12 detoxified cocaine abusers and in 20 controls to evaluate if there were changes in cocaine binding and in dopamine (DA) transporter availability assocd. with chronic cocaine use. Nine controls and 10 cocaine abusers had an addnl. scan with [18F]N-methylspiroperidol to measure dopamine D2 receptors. Cocaine abusers had significantly lower uptake of [11C]cocaine in brain (6.2% dose/mL tissues) than controls (7.7%). The distribution vols. (DV) for [11C]cocaine were reduced in basal ganglia (BG), cortex, thalamus, and cerebellum (CB) of cocaine abusers. However there were no differences in the ratio of the DV in BG to that in CB, which is an est. of DA transporter availability. Values for DA D2 receptor availability were decreased in cocaine abusers and did not correlate with ests. of dopamine transporter availability. In summary, detoxified cocaine abusers showed decreased uptake of cocaine in brain but did not show changes in DA transporter availability.245Volkow, N. D.; Fowler, J. S.; Wang, G.-J. Positron emission tomography and single-photon emission computed tomography in substance abuse research. Semin. Nucl. Med. 2003, 33, 114– 128, DOI: 10.1053/snuc.2003.127300[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s3jsVantA%253D%253D&md5=18cc4941c3f3e129f551705c518d29bcPositron emission tomography and single-photon emission computed tomography in substance abuse researchVolkow Nora D; Fowler Joanna S; Wang Gene-JackSeminars in nuclear medicine (2003), 33 (2), 114-28 ISSN:0001-2998.Many advances in the conceptualization of addiction as a disease of the brain have come from the application of imaging technologies directly in the human drug abuser. New knowledge has been driven by advances in radiotracer design and chemistry and positron emission tomography (PET) and single-photon emission computed tomography (SPECT) instrumentation and the integration of these scientific tools with the tools of biochemistry, pharmacology, and medicine. This topic cuts across the medical specialties of neurology, psychiatry, oncology, and cardiology because of the high medical, social, and economic toll that drugs of abuse, including the legal drugs, cigarettes and alcohol, take on society. This article highlights recent advances in the use of PET and SPECT imaging to measure the pharmacokinetic and pharmacodynamic effects of drugs of abuse on the human brain.246Ginovart, N. PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington’s disease. Brain. 1997, 120, 503– 514, DOI: 10.1093/brain/120.3.503[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3ntFWisg%253D%253D&md5=b2bfd52318bc0781af3c4a05b9a3a7f0PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's diseaseGinovart N; Lundin A; Farde L; Halldin C; Backman L; Swahn C G; Pauli S; Sedvall GBrain : a journal of neurology (1997), 120 ( Pt 3) (), 503-14 ISSN:0006-8950.PET and: markers for the pre- and postsynaptic neurons were used to study the dopamine system in vivo in Huntington's disease. The radioligands used were [11C]SCH 23390 for D1-receptors, [11C]raclopride for D2-receptors and [11C]beta-CIT for dopamine transporters. Five patients with Huntington's disease and five matched controls were recruited. Brain anatomy was examined by MRI. The findings in patients were as follows. Postsynaptic D1- and D2-receptor densities were similarly reduced in the striatum. A reduction in D1-receptor density was shown in the temporal cortex; it draws attention to the cortical degeneration in relation to the cognitive deficits observed in Huntington's disease. The reduction of D1- and D2-receptor binding potentials in the striatum correlated significantly with increasing duration of illness. The correlation between the duration of illness and decline of D1- and D2-receptors make these receptors valuable as quantitative markers for the Huntington's disease degenerative process. Besides postsynaptic changes, a significant 50% decrease of [11C]beta-CIT binding to the dopamine transporter was found in the striatum. A reduced striatal blood flow in Huntington's disease cannot be excluded and could account for a small part of the decrease in [11C]beta-CIT binding. We suggest that the finding reflects a loss of presynaptic terminals or a reduced expression of dopamine transporter in the nigrostriatal dopaminergic system in Huntington's disease.247Halldin, C.; Erixon-Lindroth, N.; Pauli, S.; Chou, Y.-H.; Okubo, Y.; Karlsson, P.; Lundkvist, C.; Olsson, H.; Guilloteau, D.; Emond, P.; Farde, L. [(11)C]PE2I: A highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 1220– 1230, DOI: 10.1007/s00259-003-1212-3[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXms12hurk%253D&md5=ad443ce95c326ce909c87aaf36ea0b6d[11C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brainHalldin, Christer; Erixon-Lindroth, Nina; Pauli, Stefan; Chou, Yuan-Hwa; Okubo, Yoshiro; Karlsson, Per; Lundkvist, Camilla; Olsson, Hans; Guilloteau, Denis; Emond, Patrick; Farde, LarsEuropean Journal of Nuclear Medicine and Molecular Imaging (2003), 30 (9), 1220-1230CODEN: EJNMA6; ISSN:1619-7070. (Springer-Verlag)The aim of this study was to explore the potential of a new selective dopamine transporter (DAT) compd. as a radioligand for positron emission tomog. (PET) examn. of DAT in the human brain. The high affinity DAT compd. N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane (PE2I) was radiolabeled by the O-methylation approach and the binding was characterized by PET in cynomolgus monkeys and a healthy man. Metabolite levels in plasma were measured by gradient high-performance liq. chromatog. O-methylation of the corresponding free acid precursor with [11C]methyl triflate gave high radiochem. yield (80%) and specific radioactivity (55 GBq/μmol). [11C]PE2I binding in cynomolgus monkeys was nine times higher in the striatum than in the cerebellum at peak equil., which appeared 55-65 min after injection. Displacement and pretreatment measurements using unlabeled β-CIT, GBR 12909, cocaine, citalopram and maprotiline confirmed that [11C]PE2I binds selectively to DAT. In a preliminary study in one human subject the radioactivity ratios of the striatum and substantia nigra to the cerebellum were 10 and 1.8, resp., at peak equil., which appeared at 40-50 min and 20 min, resp., after injection. The fraction of the total radioactivity in monkey and human plasma representing unchanged [11C]PE2I was 15-20% at 40 min after injection. The present characterization of binding in monkey and man suggests that [11C]PE2I is a suitable PET radioligand for quant. regional examn. of DAT in man.248Varrone, A.; Tóth, M.; Steiger, C.; Takano, A.; Guilloteau, D.; Ichise, M.; Gulyás, B.; Halldin, C. Kinetic analysis and quantification of the dopamine transporter in the nonhuman primate brain with 11C-PE2I and 18F-FE-PE2I. J. Nucl. Med. 2011, 52, 132– 139, DOI: 10.2967/jnumed.110.077651[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtleisLo%253D&md5=6c474e7036add7329c257c89f09b763cKinetic analysis and quantification of the dopamine transporter in the nonhuman primate brain with 11C-PE2I and 18F-FE-PE2IVarrone, Andrea; Toth, Miklos; Steiger, Carsten; Takano, Akihiro; Guilloteau, Denis; Ichise, Masanori; Gulyas, Balazs; Halldin, ChristerJournal of Nuclear Medicine (2011), 52 (1), 132-139CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl)nortropane (18F-FE-PE2I) is a novel radioligand for dopamine transporter (DAT) PET. As compared with 11C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane (11C-PE2I), 18F-FE-PE2I shows faster kinetics and more favorable metab., with less prodn. of a radiometabolite with intermediate lipophilicity (M1), which-in the case of 11C-PE2I-has been shown to enter the rat brain. In this study, we compared DAT quantification with 11C-PE2I and 18F-FE-PE2I in nonhuman primates, using kinetic and graphical anal. with the input function of both the parent and the radiometabolite, to assess the potential contribution of the radiometabolite. Methods: Three rhesus monkeys were examd. with 11C-PE2I and 18F-FE-PE2I using the HRRT system. Arterial input functions of the parent and radiometabolite M1 were measured. Kinetic and graphical analyses were applied using either the parent input (methods 1 and 3) or the parent plus radiometabolite input (methods 2 and 4). Outcome measures were distribution vols. (VT and VND), specific-to-nondisplaceable tissue radioactivity ratio at equil. (BPND; parent input), and specific-to-nondisplaceable tissue radioactivity ratio at equil. in the presence of metabolites (RT; parent plus radiometabolite input). Results: 11C-PE2I showed higher distribution vols. than 18F-FE-PE2I calcd. with methods 1 and 3 (striatal VT, ∼300%; VND in cerebellum, ∼30%). With methods 2 and 4, VT in the striatum was approx. 60% higher in the case of 11C-PE2I, whereas no difference in VND was found in the cerebellum. For each radioligand, BPND estd. with methods 1 and 3 tended to be higher than RT estd. with methods 2 and 4. However, the bias of BPND, compared with RT, was much larger for 11C-PE2I (40%-60% in the caudate and putamen) than for 18F-FE-PE2I (<10% in the caudate and putamen). Conclusion: The direct comparison between the radioligands confirmed that 18F-FE-PE2I shows faster kinetics and more favorable metab. than 11C-PE2I. The kinetic and graphical analyses with the input function of the parent and radiometabolite showed that the bias in BPND was much lower for 18F-FE-PE2I than for 11C-PE2I and suggested that the lower prodn. of the radiometabolite M1 would make 18F-FE-PE2I more suitable for the DAT quantification. Further studies in humans are necessary to confirm these findings.249Jonasson, M.; Appel, L.; Danfors, T.; Nyholm, D.; Askmark, H.; Frick, A.; Engman, J.; Furmark, T.; Sörensen, J.; Lubberink, M. Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction. Am. J. Nucl. Med. Mol. Imaging 2017, 7, 263– 274[PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmvVSjt7c%253D&md5=960adbbcc5e146f5a0f079a835f2c79dDevelopment of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extractionJonasson, My; Appel, Lieuwe; Danfors, Torsten; Nyholm, Dag; Askmark, Haakan; Frick, Andreas; Engman, Jonas; Furmark, Tomas; Soerensen, Jens; Lubberink, MarkAmerican Journal of Nuclear Medicine and Molecular Imaging (2017), 7 (6), 263-275CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)[11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clin. application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum ref. region defined on a co-registered MRI, as well as a supervised cluster anal. (SVCA)-based ref. Initial 20, 30 and 40 min of the scans were extd. and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based ref. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extn. of a ref. region. These outcomes will support routine applications of [11C]PE2I PET in clin. settings.250Appel, L.; Jonasson, M.; Danfors, T.; Nyholm, D.; Askmark, H.; Lubberink, M.; Sorensen, J. Use of 11C-PE2I PET in differential diagnosis of parkinsonian disorders. J. Nucl. Med. 2015, 56, 234– 242, DOI: 10.2967/jnumed.114.148619[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislOgs74%253D&md5=30000cf5b125758031db5a97314fda6eUse of 11C-PE2I PET in differential diagnosis of parkinsonian disordersAppel, Lieuwe; Jonasson, My; Danfors, Torsten; Nyholm, Dag; Askmark, Haakan; Lubberink, Mark; Soerensen, JensJournal of Nuclear Medicine (2015), 56 (2), 234-242/1-234-242/9, 9 pp.CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clin. diagnosis. A dual examn. using 123I-FP-CIT (123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane, or 123I-ioflupane) SPECT and 18F-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, resp. Parametric images based on a single, dynamic 11C-PE2I (N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methyl-phenyl)nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R1]) at voxel level. This study aimed to evaluate the validity of 11C-PE2I PET against the dual-modality approach using 123I-FP-CIT SPECT and 18F-FDG PET. Methods: Sixteen patients with parkinsonian disorders had a dual examn. with 18F-FDG PET and 123I-FP-CIT SPECT following clin. routines and addnl. an exptl. 11C-PE2I PET scan. Parametric BPND and R1 images were generated using receptor parametric mapping with the cerebellum as a ref. T1-weighted MR imaging was used for automated definition of vols. of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examd. using VOIs across the brain. BPND and R1 values were compared with normalized 123I-FP-CIT and 18F-FDG uptake values, resp., using Pearson correlations and regression analyses. In addn., 2 masked interpreters evaluated the images visually, in both the routine and the exptl. datasets, for comparison of patient diagnoses. Results: Parametric 11C-PE2I BPND and R1 images showed high consistency with 123I-FP-CIT SPECT and 18F-FDG PET images. Correlations between 11C-PE2I BPND and 123I-FP-CIT uptake ratios were 0.97 and 0.76 in the putamen and caudate nucleus, resp. Regional 11C-PE2I R1 values were moderately to highly correlated with normalized 18F-FDG values (range, 0.61-0.94). Visual assessment of DAT availability showed a high consistency between 11C-PE2I BPND and 123I-FP-CIT images, whereas the consistency was somewhat lower for appraisal of overall brain functional activity using 123I-FP-CIT and 18F-FDG images. Substantial differences were found between clin. diagnosis and both neuroimaging diagnoses. Conclusion: A single, dynamic 11C-PE2I PET investigation is a powerful alternative to a dual examn. with (123)I-FP-CIT SPECT and (18)F-FDG PET for differential diagnosis of parkinsonian disorders. A large-scale patient study is, however, needed to further investigate distinct pathol. patterns in overall brain functional activity for various parkinsonian disorders.251Fazio, P.; Svenningsson, P.; Forsberg, A.; Jönsson, E. G.; Amini, N.; Nakao, R.; Nag, S.; Halldin, C.; Farde, L.; Varrone, A. Quantitative analysis of 18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4’-methyl-phenyl) nortropane binding to the dopamine transporter in Parkinson disease. J. Nucl. Med. 2015, 56, 714– 720, DOI: 10.2967/jnumed.114.152421[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFakt7%252FF&md5=61a35862f29aea0314570cd128ef8677Quantitative analysis of 18F-(E)-N-(3-iodoprop-2-enyl)-2β-Carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane binding to the dopamine transporter in Parkinson diseaseFazio, Patrik; Svenningsson, Per; Forsberg, Anton; Joensson, Erik G.; Amini, Nahid; Nakao, Ryuji; Nag, Sangram; Halldin, Christer; Farde, Lars; Varrone, AndreaJournal of Nuclear Medicine (2015), 56 (5), 714-720CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane (18F-FE-PE2I) is a recently developed radioligand for the in vivo quantification of the dopamine transporter (DAT) in the striatum and substantia nigra (SN). The aim of this study was to examine the suitability of 18F-FE-PE2I as a tool for imaging the nigrostriatal pathway in Parkinson disease (PD) with PET. Methods: Ten PD patients (9 men and 1 woman; mean age ± SD, 60 ± 9 y; Hoehn and Yahr, 1-2; Unified Parkinson Disease Rating Scale motor, 18.9 ± 6.7) and 10 controls (9 men and 1 woman; mean age ± SD, 60 ± 7 y) were included. PET measurements with 18F-FE-PE2I were conducted for 93 min using the High-Resoln. Research Tomograph. Venous blood was drawn to compare protein binding, parent fraction, and radiometabolite compn. in PD patients and controls. Regions of interest for the caudate, putamen, ventral striatum, SN, and cerebellum were drawn on coregistered MR images. The outcome measure was the binding potential (BPND) estd. with the simplified ref. tissue model and the Logan graphical anal., using the cerebellum as a ref. region. Time stability of BPND was examd. to define the shortest acquisition protocol for quant. studies. The wavelet-aided parametric imaging method was used to obtain high-resoln. BPND images to compare DAT availability in the striatum and SN in PD patients and control subjects. Group differences were assessed with the unpaired t test (P < 0.05). Results: Parent, radiometabolite fractions, plasma concn., and cerebellar uptake of 18F-FE-PE2I did not differ significantly between PD patients and controls. Stable ests. of BPND (<8% of the 93-min value) were obtained with the simplified ref. tissue model using approx. 66 min of data. BPND values in PD patients were significantly lower than those in controls (P < 0.05) in the caudate (2.54 ± 0.79 vs. 3.68 ± 0.56), putamen (1.39 ± 1.04 vs. 4.41 ± 0.54), ventral striatum (2.26 ± 0.93 vs. 3.30 ± 0.46), and SN (0.46 ± 0.20 vs. 0.68 ± 0.15). Conclusion: 18F-FE-PE2I is clearly a suitable radioligand for DAT quantification and imaging of the nigrostriatal pathway in PD. Similar metab. in controls and PD patients, suitability of the cerebellum as a ref. region, and accuracy of quantification using approx. 66 min of PET data are advantages for noninvasive and simplified imaging protocols for PD studies. Finally, DAT loss in PD can be measured in both the striatum and the SN, supporting the utility of 18F-FE-PE2I as an imaging tool of the nigrostriatal pathway.252Frey, K. A.; Koeppe, R. A.; Kilbourn, M. R.; Vander Borght, T. M.; Albin, R. L.; Gilman, S.; Kuhl, D. E. Presynaptic monoaminergic vesicles in Parkinson’s disease and normal aging. Ann. Neurol. 1996, 40, 873– 884, DOI: 10.1002/ana.410400609[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7lvFGktA%253D%253D&md5=f1a19f1066caaeb4bbd9988575201ef6Presynaptic monoaminergic vesicles in Parkinson's disease and normal agingFrey K A; Koeppe R A; Kilbourn M R; Vander Borght T M; Albin R L; Gilman S; Kuhl D EAnnals of neurology (1996), 40 (6), 873-84 ISSN:0364-5134.We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [11C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug- or lesion-compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood-brain [11C]DTBZ transport (K1) and VMAT2 binding site density (tissue-to-plasma DTBZ distribution volume, DV) from the cerebral and plasma DTBZ time courses after intravenous tracer injection. In controls, we found reductions of putamen DTBZ DVwith advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (-61%) and in the caudate nucleus (-43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [11C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.253Frey, K. A.; Koeppe, R. A.; Kilbourn, M. R. Imaging the vesicular monoamine transporter. Adv. Neurol. 2001, 86, 237– 247[PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjvFKhsrY%253D&md5=4847b93eeb0a633fb996e1970f2a4b51Imaging the vesicular monoamine transporterFrey, Kirk A.; Koeppe, Robert A.; Kilbourn, Michael R.Advances in Neurology (2001), 86 (Parkinson's Disease), 237-247CODEN: ADNRA3; ISSN:0091-3952. (Lippincott-Raven Publishers)A review with 79 refs. Parkinson's disease (PD), proposed formally as a neurol. syndrome in 1817 by James Parkinson, remains today the most common neurodegenerative disease of movement and the second most common neurodegenerative disorder after Alzheimer's disease. The cardinal symptoms of PD affect voluntary movement, consisting of bradykinesia and rigidity together with a resting tremor. Although detailed population-based data are lacking, ests. of its prevalence in the Unites States run between 250,000 and in excess of 500,000 cases, with an annual incidence of 14/100,000. The incidence of PD increases with age in 'adulthood, peaking between ages 55 and 60. The no. of PD patients in the United States is projected to increase over fourfold in the next half-century on the basis of an increasing aged population. In the ongoing search for neuroprotective, disease-modifying PD therapies, availability of an objective, quant. marker of nigrostriatal-damage will be essential to assess outcome and endpoints.254Bohnen, N. I.; Koeppe, R. A.; Meyer, P.; Ficaro, E.; Wernette, K.; Kilbourn, M. R.; Kuhl, D. E.; Frey, K. A.; Albin, R. L. Decreased striatal monoaminergic terminals in Huntington disease. Neurology 2000, 54, 1753– 1759, DOI: 10.1212/WNL.54.9.1753[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3msVCntA%253D%253D&md5=ec7bc5ed0d2fa21714147924a4567276Decreased striatal monoaminergic terminals in Huntington diseaseBohnen N I; Koeppe R A; Meyer P; Ficaro E; Wernette K; Kilbourn M R; Kuhl D E; Frey K A; Albin R LNeurology (2000), 54 (9), 1753-9 ISSN:0028-3878.OBJECTIVE: To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). BACKGROUND: Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. METHODS: Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. RESULTS: The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.255Shi, X.; Zhang, Y.; Xu, S.; Kung, H. F.; Qiao, H.; Jiang, L.; Zhu, L.; Guo, Q.; Yi, C.; Luo, G.; Wu, L.; Pei, Z.; Wang, J.; Zhang, X.; Chen, L. Decreased striatal vesicular monoamine transporter type 2 correlates with the nonmotor symptoms in Parkinson disease. Clinical Nuclear Medicine. 2019, 44, 707– 713, DOI: 10.1097/RLU.0000000000002664[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M3ntlCkug%253D%253D&md5=2a9ac0fb0766f85cc7ae44c43db91c0bDecreased Striatal Vesicular Monoamine Transporter Type 2 Correlates With the Nonmotor Symptoms in Parkinson DiseaseShi Xinchong; Yi Chang; Luo Ganhua; Zhang Xiangsong; Zhang Yan; Zhu Lin; Xu Shaohua; Jiang LuLu; Guo Qiyi; Wu Lei; Pei Zhong; Chen Ling; Kung Hank F; Qiao Hongwen; Wang JianClinical nuclear medicine (2019), 44 (9), 707-713 ISSN:.OBJECTIVE: Nonmotor symptoms (NMS) are critical players in the patients' quality of life in Parkinson disease (PD). Vesicular monoamine transporter type 2 (VMAT2) has been reported owing to a role in affecting dopamine neurons in the striatum. Therefore, this study set out to characterize the relationship between VMAT2 distribution in the striatum in relation to the NMS in PD. METHODS: Totally, 21 age-matched normal controls and 37 patients with PD in the moderate stages were included, followed by examination using F-DTBZ (F-AV133) PET/CT. The specific uptake ratio (SUR) of each striatal subregion was then determined with the occipital cortex as the reference background region. The overall NMSs of each individual patient were evaluated. Finally, the role of the striatal SURs in the clinical symptom scores were evaluated through the application of a Spearman correlation analysis as well as a multivariable stepwise regression analysis. RESULTS: Patients with PD, particularly those at a more advanced stage, exhibited a more pronounced reduction in SURs in the bilateral putamen and caudate nucleus (P < 0.05, vs healthy controls). Meanwhile, patients at more advanced PD stages were found to have significantly worse scores in NMS except cognitive function. The Spearman correlation analysis demonstrated that NMS scores, with the exception of cognition scores, were correlated with striatal SURs (P < 0.05). CONCLUSION: The key findings of the study identified a correlation between decreased striatal VMAT2 with a broad spectrum of NMS in patients with PD, highlighting the association between diminished dopamine supply and the development of NMS in PD.256Cho, S. S.; Christopher, L.; Koshimori, Y.; Li, C.; Lang, A. E.; Houle, S.; Strafella, A. P. Decreased pallidal vesicular monoamine transporter type 2 availability in Parkinson’s disease: The contribution of the nigropallidal pathway. Neurobiol. Dis. 2019, 124, 176– 182, DOI: 10.1016/j.nbd.2018.11.022[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlensLbO&md5=f0cc4962ad2e2c7d3f54f737f2701acdDecreased pallidal vesicular monoamine transporter type 2 availability in Parkinson's disease: The contribution of the nigropallidal pathwayCho, Sang Soo; Christopher, Leigh; Koshimori, Yuko; Li, Crystal; Lang, Anthony E.; Houle, Sylvain; Strafella, Antonio P.Neurobiology of Disease (2019), 124 (), 176-182CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)To date, the contribution of the nigropallidal pathway degeneration to Parkinson's disease (PD) motor symptoms has received little attention and is generally poorly understood in spite of solid evidence that the globus pallidus (GP) receives a dense neuronal projection from the substantia nigra. To explore the dopaminergic (DA) changes of the GP in PD, we measured the availability of vesicular monoamine transporter 2 (VMAT2) using [11C]DTBZ and positron emission tomog. in 30 PD patients and 12 controls. PD patients were classified in two groups based on severity of disease. VMAT2 redn. was found to be significant in the external GP (GPe) regardless of the disease stage, while the internal GP (GPi) showed redn. only in more severe patients. Pallidal VMAT2 binding correlated with dopaminergic changes in the striatum, with the GPe showing a stronger assocn. than GPi. Our findings showed DA terminals in the GPe and GPi may be differentially vulnerable in different stages of the disease, possibly playing a distinctive role in the development of motor complications with GPi DA deficiency contributing more to later-stage symptoms.257Lin, K.-J.; Weng, Y.-H.; Wey, S.-P.; Hsiao, I.-T.; Lu, C.-S.; Skovronsky, D.; Chang, H.-P.; Kung, M.-P.; Yen, T.-C. Whole-body biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): A novel vesicular monoamine transporter 2 imaging agent. J. Nucl. Med. 2010, 51, 1480– 1485, DOI: 10.2967/jnumed.110.078196[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1ejsLjM&md5=50db85e8ecfbb8824968523a88078a93Whole-body biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): a novel vesicular monoamine transporter 2 imaging agentLin, Kun-Ju; Weng, Yi-Hsin; Wey, Shiaw-Pyng; Hsiao, Ing-Tsung; Lu, Chin-Song; Skovronsky, Daniel; Chang, Hsiu-Ping; Kung, Mei-Ping; Yen, Tzu-ChenJournal of Nuclear Medicine (2010), 51 (9), 1480-1485CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-18F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7, 11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (18F-FP-(+)-dihydrotetrabenazine [DTBZ] or 18F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clin. use. 9 Healthy human subjects (mean age ± SD, 58.6 ± 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 ± 22.9 MBq of 18F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to det. the equiv. dose for individual organs. The radiotracer did not show any noticeable adverse effects for the 9 subjects examd. The radioactivity uptake in the brain was the highest at 7.5% ± 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 ± 23.8 μGy/MBq, was the pancreas. The ED equiv. and ED for 18F-AV-133 were 36.5 ± 2.8 and 27.8 ± 2.5 μSv/MBq, resp. These values are comparable to those reported for any other 18F-labeled radiopharmaceutical. 18F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans.258Lin, S.-C.; Lin, K.-J.; Hsiao, I.-T.; Hsieh, C.-J.; Lin, W.-Y.; Lu, C.-S.; Wey, S.-P.; Yen, T.-C.; Kung, M.-P.; Weng, Y.-H. In vivo detection of monoaminergic degeneration in early Parkinson disease by 18F-9-fluoropropyl-(+)-dihydrotetrabenzazine PET. J. Nucl. Med. 2014, 55, 73– 79, DOI: 10.2967/jnumed.113.121897[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlCktb0%253D&md5=c8ab5ea97ec3bcfa43803bb0debed2faIn vivo detection of monoaminergic degeneration in early Parkinson disease by 18F-9-fluoropropyl-(+)- dihydrotetrabenzazine PETLin, Shao-Cheng; Lin, Kun-Ju; Hsiao, Ing-Tsung; Hsieh, Chia-Ju; Lin, Wey-Yil; Lu, Chin-Song; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Kung, Mei-Ping; Weng, Yi-HsinJournal of Nuclear Medicine (2014), 55 (1), 73-79CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)PET with 18F-9-fluoropropyl-(+)-dihydrotetrabenzazine (18F-DTBZ), a novel radiotracer targeting vesicular monoamine transporter type 2 (VMAT2), has been proven as a useful imaging marker to measure dopaminergic integrity. Methods: The aim of this study was to evaluate the capability of 18F-DTBZ PET in detecting the monoaminergic degeneration in early Parkinson disease (PD) in vivo. Seventeen age-matched healthy subjects and 30 PD patients at early stage of disease (duration of disease ≤ 5 y) with mild and unilateral motor symptoms underwent 18F-DTBZ PET scans. The severity of disease, including Unified Parkinson Disease Rating Scale and modified Hoehn and Yahr Stage (mHY), were recorded at off-medication states. The standardized vols. of interest were applied to the spatial normalized image for quantification anal. The specific uptake ratios (SURs) were calcd. according to the formula (sp. vol.s-of-interest counts/occipital cortex counts) - 1. SUR measurements were summarized for each brain region. Results: The mean duration of disease in the PD group was 3.2 ± 2.1 y (range, 0.5-5 y). The mean mHY was 1.0 ± 0.1 (range, 1-1.5). The SURs of bilateral caudate, anterior putamen, posterior putamen, substantia nigra, and nucleus accumbens were significantly lower in PD patients than those of healthy subjects. The redn. of SURs was most severe in the contralateral (the brain regions that are located opposite to the symptomatic side) posterior putamen (-81%), followed by the ipsilateral posterior putamen (-67%). Receiver-operating-characteristic curve anal. showed that the SURs of the bilateral posterior putamen and contralateral anterior putamen had a sensitivity of 100% and specificity of 100% in differentiating PD patients from healthy subjects. Conclusion: 18F-DTBZ PET was as an excellent tool for the early diagnosis of PD. The obvious decline of 18F-DTBZ uptake in the ipsilateral (asymptomatic) striatum suggested that 18F-DTBZ PET might serve as an in vivo biomarker to detect the monoaminergic degeneration in the premotor phase of PD.259Siderowf, A.; Pontecorvo, M. J.; Shill, H. A.; Mintun, M. A.; Arora, A.; Joshi, A. D.; Lu, M.; Adler, C. H.; Galasko, D.; Liebsack, C.; Skovronsky, D. M.; Sabbagh, M. N. PET imaging of amyloid with florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer’s disease and lewy body disorders. BMC Neurol. 2014, 14, 79, DOI: 10.1186/1471-2377-14-79[Crossref], [PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs12hu73I&md5=2ddbc39cbf60e79d484438a86411ac88PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer's disease and Lewy body disordersSiderowf, Andrew; Pontecorvo, Michael J.; Shill, Holly A.; Mintun, Mark A.; Arora, Anupa; Joshi, Abhinay D.; Lu, Ming; Adler, Charles H.; Galasko, Douglas; Liebsack, Carolyn; Skovronsky, Daniel M.; Sabbagh, Marwan N.BMC Neurology (2014), 14 (), 79/1-79/9, 9CODEN: BNMEC8; ISSN:1471-2377. (BioMed Central Ltd.)Background: Biomarkers based on the underlying pathol. of Alzheimer's disease AD and Dementia with Lewy Bodies DLB have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson's disease PD using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 florbenazine, a marker for vesicular monamine type 2 transporters VMAT2. Methods: Patients with DLB and AD, Parkinson's disease PD and healthy controls HC were recruited for this study. On sep. days, subjects received i.v. injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 d. were assessed quant. and by binary clin. interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathol. AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding and correlated with measures of cognition and parkinsonism. Results: 11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group n = 21 compared to the PD/HC groups n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006. VMAT2 d. was significantly lower in the PD/DLB group n = 16 compared to the AD/ HC group n = 15; 1.83 vs. 2.97; p < 0.0001. Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding r = 0.73; p = 0.011. Conclusions: The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathol.260Lin, K.-J.; Weng, Y.-H.; Hsieh, C.-J.; Lin, W.-Y.; Wey, S.-P.; Kung, M.-P.; Yen, T.-C.; Lu, C.-S.; Hsiao, I.-T. Brain imaging of vesicular monoamine transporter type 2 in healthy aging subjects by 18F-FP-(+)-DTBZ PET. PLoS One 2013, 8, e75952 DOI: 10.1371/journal.pone.0075952[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFOnur%252FK&md5=69c5d3017ba1d87098ba96ee7422d7ecBrain imaging of vesicular monoamine transporter type 2 in healthy aging subjects by 18F-FP-(+)-DTBZ PETLin, Kun-Ju; Weng, Yi-Hsin; Hsieh, Chia-Ju; Lin, Wey-Yil; Wey, Shiaw-Pyng; Kung, Mei-Ping; Yen, Tzu-Chen; Lu, Chin-Song; Hsiao, Ing-TsungPLoS One (2013), 8 (9), e75952CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)18F-FP-(+)-DTBZ is a novel PET radiotracer targeting vesicular monoamine transporter type 2 (VMAT2). The goal was to explore the image features in normal human brains with 18F-FP-(+)-DTBZ as a ref. of mol. landmark for clin. diagnosis in Parkinson's disease (PD) and related disorders. Materials and Methods: A total of 22 healthy subjects (59.3 ± 6.0 years old) including 7 men and 15 women were recruited for MRI and 18F-FP-(+)-DTBZ PET scans. A total no. of 55 brain VOIs were selected for quantitation anal. The regional specific uptake ratio (SUR) was calcd. with occipital as ref. from MRI-based spatially normalized 18F-FP-(+)-DTBZ images. Regional percentage SUR to that of anterior putamen was calcd. Av. SUR images were displayed in 2D and 3D space to illustrate the image patterns. The correlation between age and regional VMAT2 uptake was also examd. Results: Visual assessment showed sym. uptake of 18F-FP-(+)-DTBZ and obviously highest in striatum, followed by nucleus accumbens, hypothalamus, substantia nigra, and raphe nuclei. Quantification anal. revealed striatal VMAT2 d. of anterior putamen > posterior putamen > caudate nucleus. Other subcortical regions were with moderate VMAT2 distribution (6∼51 % SUR of anterior putamen), while slightly lower VMAT2 was obsd. in cerebellum (10.60% SUR) and much lower in neocortex (<5% SUR). No significant correlation of SUR to age was found in subcortical regions. Conclusion: Using 18F-FP-(+)-DTBZ PET, we showed the 2D and 3D imaging features of the VMAT2 distribution in vivo in healthy aging brains. The in vivo imaging characteristics of VMAT2 is consistent with the expression of VMAT2 in a recent autopsy study. Therefore, 3D visualization and higher image quality of 18F-FP-(+)-DTBZ PET imaging might potentially be a powerful biomarker in detecting VMAT2 distribution of subcortical regions, and for Parkinson's disease and related neuropsychiatric disorders involving related monoaminergic systems.261Wu, X.; Zhou, X.; Zhang, S.; Zhang, Y.; Deng, A.; Han, J.; Zhu, L.; Kung, H. F.; Qiao, J. Brain uptake of a non-radioactive pseudo-carrier and its effect on the biodistribution of [18F]AV-133 in mouse brain. Nucl. Med. Biol. 2015, 42, 630– 636, DOI: 10.1016/j.nucmedbio.2015.03.009[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmvFaqtrk%253D&md5=c0a6295f32186fc2a61f8cafdbd25f19Brain uptake of a non-radioactive pseudo-carrier and its effect on the biodistribution of [18 F]AV-133 in mouse brainWu, Xianying; Zhou, Xue; Zhang, Shuxian; Zhang, Yan; Deng, Aifang; Han, Jie; Zhu, Lin; Kung, Hank F.; Qiao, JinpingNuclear Medicine and Biology (2015), 42 (7), 630-636CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)9-[18 F]Fluoropropyl-(+)-dihydrotetrabenazine ([18 F]AV-133) is a new PET imaging agent targeting vesicular monoamine transporter type II (VMAT2). To shorten the prepn. of [18 F]AV-133 and to make it more widely available, a simple and rapid purifn. method using solid-phase extn. (SPE) instead of high-pressure liq. chromatog. (HPLC) was developed. The SPE method produced doses contg. the non-radioactive pseudo-carrier 9-hydroxypropyl-(+)-dihydrotetrabenazine (AV-149). The objectives of this study were to evaluate the brain uptake of AV-149 by UPLC-MS/MS and its effect on the biodistribution of [18 F]AV-133 in the brains of mice. The mice were injected with a bolus including [18 F]AV-133 and different doses of AV-149. Brain tissue and blood samples were harvested. The effect of different amts. of AV-149 on [18 F]AV-133 was evaluated by quantifying the brain distribution of radiolabeled tracer [18 F]AV-133. The concns. of AV-149 in the brain and plasma were analyzed using a UPLC-MS/MS method. The concns. of AV-149 in the brain and plasma exhibited a good linear relationship with the doses. The receptor occupancy curve was fit, and the calcd. ED50 value was 8.165 mg/kg. The brain biodistribution and regional selectivity of [18 F]AV-133 had no obvious differences at AV-149 doses lower than 0.1 mg/kg. With increasing doses of AV-149, the brain biodistribution of [18 F]AV-133 changed significantly. The results are important to further support that the improved radiolabelling procedure of [18 F]AV-133 using an SPE method may be suitable for routine clin. application.262Huang, Z.-R.; Tsai, C.-L.; Huang, Y.-Y.; Shiue, C.-Y.; Tzen, K.-Y.; Yen, R.-F.; Hsin, L.-W. A novel potential positron emission tomography imaging agent for vesicular monoamine transporter type 2. PLoS One 2016, 11, e0161295 DOI: 10.1371/journal.pone.0161295[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFCisLw%253D&md5=f3bd19ae6fabfc5f9bb0cd9e7bb82d58A novel potential positron emission tomography imaging agent for vesicular monoamine transporter type 2Huang, Zih-Rou; Tsai, Chia-Ling; Huang, Ya-Yao; Shiue, Chyng-Yann; Tzen, Kai-Yuan; Yen, Ruoh-Fang; Hsin, Ling-WeiPLoS One (2016), 11 (9), e0161295/1-e0161295/11CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)In the early 1990s, 9-(+)-11C-dihydrotetrabenazine (9-(+)-11C-DTBZ) was shown to be a useful positron emission tomog. (PET) imaging agent for various neurodegenerative disorders. Here, we described the radiosynthesis and evaluation of the 9-(+)-11C-DTBZ analog, 10-(+)-11C-DTBZ, as a vesicular monoamine transporter 2 (VMAT2) imaging agent and compare it with 9-(+)-11C-DTBZ. 10-(+)-11C-DTBZ was obtained by 11C-MeI methylation with its 10 hydroxy precursor in the presence of 5 M NaOH. It had a slightly better av. radiochem. yield of 35.3 ± 3.6% (decay-cor. to end of synthesis (EOS)) than did 9-(+)-11C-DTBZ (30.5 ± 2.3%). MicroPET studies showed that 10-(+)-11C-DTBZ had a striatum-to-cerebellum ratio of 3.74 ± 0.21 at 40 min post-injection, while the ratio of 9-(+)-11C-DTBZ was 2.50 ± 0.33. This indicated that 10-(+)-11C-DTBZ has a higher specific uptake in VMAT2-rich brain regions, and 10-(+)-11C-DTBZ may be a potential VMAT2 radioligand. Our expt. is the first study of 10-(+)-11C-DTBZ to include dynamic brain distribution in rat brains.263Fowler, J. S.; Ding, Y.-S.; Volkow, N. D. Radiotracers for positron emission tomography imaging. Semin. Nucl. Med. 2003, 33, 14– 27, DOI: 10.1053/snuc.2003.127297[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252Fptlaksg%253D%253D&md5=eb47eff3d2a3e6b23507ddb9fa08eec8Radiotracers for positron emission tomography imagingFowler Joanna S; Ding Yu-Shin; Volkow Nora DSeminars in nuclear medicine (2003), 33 (1), 14-27 ISSN:0001-2998.Over the past 30 years, advances in radiotracer chemistry and positron emission tomography instrumentation have merged to make positron emission tomography a powerful scientific tool in the biomedical sciences. However, despite the increasing reliance of the biomedical sciences on imaging and the new needs for functional information created by the sequencing of the human genome, the development of new radiotracers with the specificity and kinetic characteristics for quantitative analysis in vivo remains a slow process. In this article, we focus on advances in the development of the radiotracers involved in neurotransmission, amino acid transport, protein synthesis, and DNA synthesis. We conclude with a brief section on newer radiotracers that image other molecular targets and conclude with a summary of some of the scientific and infrastructure needs that would expedite the development and introduction of new radiotracers into biomedical research and the practice of medicine.264Thompson, J. L.; Rosell, D. R.; Slifstein, M.; Girgis, R. R.; Xu, X.; Ehrlich, Y.; Kegeles, L. S.; Hazlett, E. A.; Abi-Dargham, A.; Siever, L. J. Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: A PET study with [11C]NNC112. Psychopharmacology. 2014, 231, 4231– 4240, DOI: 10.1007/s00213-014-3566-6[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntFGgsbo%253D&md5=e0f6076484ef954d653e07ca1c600198Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [11C]NNC112Thompson, Judy L.; Rosell, Daniel R.; Slifstein, Mark; Girgis, Ragy R.; Xu, Xiaoyan; Ehrlich, Yosefa; Kegeles, Lawrence S.; Hazlett, Erin A.; Abi-Dargham, Anissa; Siever, Larry J.Psychopharmacology (Heidelberg, Germany) (2014), 231 (21), 4231-4240CODEN: PSCHDL; ISSN:0033-3158. (Springer)Rationale: Schizotypal personality disorder (SPD) is assocd. with working memory (WM) impairments that are similar to those obsd. in schizophrenia. Imaging studies have suggested that schizophrenia is assocd. with alterations in dopamine D1 receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder. Objectives: The aim of this study was to characterize prefrontal D1 receptor availability and its relation to WM performance in SPD. Methods: We used positron emission tomog. (PET) and the radiotracer [11C]NNC112 with 18 unmedicated SPD and 21 healthy control participants; as an index of D1 receptor availability, binding potential (BP) measures (BPF, BPND, and BPP) were calcd. for prefrontal and striatal subregions. To assess WM, SPD participants completed the 2-back and Paced Auditory Serial Addn. Test (PASAT). Results: There were no significant group differences in PFC BP. BPF and BPP in the medial PFC were significantly neg. related to PASAT performance (rs = -0.551, p = .022 and rs = -0.488, p = .047, resp.), but BP was not related to 2-back performance. Conclusions: In contrast to what has been found in schizophrenia, SPD was not assocd. with significant alterations in prefrontal D1 receptor availability. Similar to previous schizophrenia findings, however, higher prefrontal D1 receptor availability was assocd. with poorer WM performance (as measured by the PASAT) in SPD. These findings suggest that schizophrenia and SPD may share a common pathophysiol. feature related to prefrontal dopamine functioning that contributes to WM dysfunction, but that in SPD, alterations in D1 may occur only in a subset of individuals and/or to an extent that is minor relative to what occurs in schizophrenia.265Abi-Dargham, A.; Xu, X.; Thompson, J. L.; Gil, R.; Kegeles, L. S.; Urban, N.; Narendran, R.; Hwang, D.-R.; Laruelle, M.; Slifstein, M. Increased prefrontal cortical D1 receptors in drug naïve patients with schizophrenia: A PET study with [11C]NNC112. J. Psychopharmacol. 2012, 26, 794– 805, DOI: 10.1177/0269881111409265[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1OksrrF&md5=4617272a99e78d7b806e4fc02d34473cIncreased prefrontal cortical D1 receptors in drug na.ovrddot.ive patients with schizophrenia: a PET study with [11C]NNC112Abi-Dargham, Anissa; Xu, Xiaoyan; Thompson, Judy L.; Gil, Roberto; Kegeles, Lawrence S.; Urban, Nina; Narendran, Raj; Hwang, Dah-Ren; Laruelle, Marc; Slifstein, MarkJournal of Psychopharmacology (London, United Kingdom) (2012), 26 (6), 794-805, 12 pp.CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)D1 receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomog. (PET) and a D1 radiotracer, [11C]NNC112, in drug na.ovrddot.ive (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, cor. for partial vol. effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial vol. effect cor. BPP measures were significantly higher in DN vs controls in cortical regions. No such increases were found in the DF vs. controls comparison. Furthermore, in the DF group, DF interval correlated pos. with cortical BPP. We conclude that upregulation of D1 receptors in schizophrenia is related to the illness itself and may be cor. and normalized by chronic antipsychotic treatment.266Poels, E. M. P.; Girgis, R. R.; Thompson, J. L.; Slifstein, M.; Abi-Dargham, A. In vivo binding of the dopamine-1 receptor PET Tracers [11C]NNC112 and [11C]SCH23390: A comparison study in individuals with schizophrenia. Psychopharmacology. 2013, 228, 167– 174, DOI: 10.1007/s00213-013-3026-8[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFOhurk%253D&md5=29c2a1212ff7abf1bcc44d34515125edIn vivo binding of the dopamine-1 receptor PET tracers [11C]NNC112 and [11C]SCH23390: a comparison study in individuals with schizophreniaPoels, Eline M. P.; Girgis, Ragy R.; Thompson, Judy L.; Slifstein, Mark; Abi-Dargham, AnissaPsychopharmacology (Heidelberg, Germany) (2013), 228 (1), 167-174CODEN: PSCHDL; ISSN:0033-3158. (Springer)Rationale: A deficit in dopamine-1 (D1) receptor function in the prefrontal cortex is suggested to play a role in the cognitive dysfunction obsd. in patients with schizophrenia. However, the results from positron emission tomog. imaging studies of D1 receptor levels in individuals with schizophrenia are mixed. Objectives: The aim of this investigation was to det. whether the in vivo characteristics of the different D1 receptor tracers used in previous reports, [11C]SCH23390 and [11C]NNC112, may have contributed to these discrepancies reported in the literature. Methods: Eight patients with schizophrenia and 12 healthy control subjects were scanned with both [11C]SCH23390 and [11C]NNC112. Results: [11C]SCH23390 and [11C]NNC112 binding potentials in both patients and control subjects were compared and no tracer by diagnosis interactions were obsd. Conclusions: The results of this study suggest that differences in the binding of [11C]SCH23390 and [11C]NNC112 obsd. in previous studies are not due to differences in the in vivo behavior of these tracers.267Plavén-Sigray, P.; Gustavsson, P.; Farde, L.; Borg, J.; Stenkrona, P.; Nyberg, L.; Bäckman, L.; Cervenka, S. Dopamine D1 receptor availability is related to social behavior: A positron emission tomography study. NeuroImage 2014, 102, 590– 595, DOI: 10.1016/j.neuroimage.2014.08.018[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSqsbnL&md5=833c660c0b51c173531cd44ea73fb8a5Dopamine D1 receptor availability is related to social behavior: A positron emission tomography studyPlaven-Sigray, Pontus; Gustavsson, Petter; Farde, Lars; Borg, Jacqueline; Stenkrona, Per; Nyberg, Lars; Baeckman, Lars; Cervenka, SimonNeuroImage (2014), 102 (Part_2), 590-595CODEN: NEIMEF; ISSN:1053-8119. (Elsevier Inc.)Dysfunctional interpersonal behavior is thought to underlie a wide spectrum of psychiatric disorders; however, the neurobiol. underpinnings of these behavioral disturbances are poorly understood. Previous mol. imaging studies have shown assocns. between striatal dopamine (DA) D2-receptor binding and interpersonal traits, such as social conformity. The objective of this study was to explore, for the first time, the role of DA D1-receptors (D1-Rs) in human interpersonal behavior.Twenty-three healthy subjects were examd. using positron emission tomog. and the radioligand [11C]SCH23390, yielding D1-R binding potential values. Striatal D1-R binding was related to personality scales selected to specifically assess one dimension of interpersonal behavior, namely a combination of affiliation and dominance (i.e., the Social Desirability, Verbal Trait Aggression and Phys. Trait Aggression scales from Swedish Universities Scales of Personality). An exploratory anal. was also performed for extrastriatal brain regions.D1-R binding potential values in the limbic striatum (r = .52; p = .015), associative striatum (r = .55; p = .009), and sensorimotor striatum (r = .67; p = .001) were pos. related to Social Desirability scores. D1-R binding potential in the limbic striatum (r = - .51; p = .019) was neg. assocd. with Phys. Trait Aggression scores. For extrastriatal regions, Social Desirability scores showed pos. correlations in the amygdala (r = .60; p = .006) and medial frontal cortex (r = .60; p = .004).This study provides further support for the role of DA function in the expression of disaffiliative and dominant traits. Specifically, D1-R availability may serve as a marker for interpersonal behavior in humans. Assocns. were demonstrated for the same dimension of interpersonal behavior as for D2-R, but in the opposite direction, suggesting that the two receptor subtypes are involved in the same behavioral processes, but with different functional roles.268Häggkvist, J.; Tóth, M.; Tari, L.; Varnäs, K.; Svedberg, M.; Forsberg, A.; Nag, S.; Dominguez, C.; Munoz-Sanjuan, I.; Bard, J.; Wityak, J.; Varrone, A.; Halldin, C.; Mrzljak, L. Longitudinal small-animal PET imaging of the zQ175 mouse model of Huntington disease shows in vivo changes of molecular targets in the striatum and cerebral cortex. J. Nucl. Med. 2017, 58, 617– 622, DOI: 10.2967/jnumed.116.180497[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmvVWrsb4%253D&md5=1d1913aa80597b5a04d7c5e803c19e00Longitudinal Small-Animal PET Imaging of the zQ175 mouse model of huntington disease shows in vivo changes of molecular targets in the striatum and cerebral cortexHaggkvist, Jenny; Toth, Miklos; Tari, Lenke; Varnas, Katarina; Svedberg, Marie; Forsberg, Anton; Nag, Sangram; Dominguez, Celia; Munoz-Sanjuan, Ignacio; Bard, Jonathan; Wityak, John; Varrone, Andrea; Halldin, Christer; Mrzljak, LadislavJournal of Nuclear Medicine (2017), 58 (4), 617-623CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Since the discovery of the HTT gene in 1993, numerous animal models have been developed to study the progression of Huntington disease (HD) and to evaluate potential new therapeutics. In the present study, we used small-animal PET to characterize the expression of mol. targets in the recently reported HD animal model, the zQ175 mouse model. Male heterozygous zQ175 (Htttm1Mfc/190JChdi, CHDI-81003003) and wild-type (WT, C57BL/6J) animals were imaged with the dopamine D2 receptor radioligand 11C-raclopride, the PDE10A radioligand 1F-MNI-659, the dopamine D receptor radioligand 11C-D1 receptor radioligand 11CNNC 112, and the 5-HT2A radioligand 11C-MDL 100907 at 6 and 9 mo of age. The outcome measure was the binding potential (BPND), using the cerebellum as the ref. region. Selected regions of interest were the striatum for all radioligands and addnl. the striatum, rostral cortex, caudal cortex, and hippocampus for 11C-NNC 112 and 11C-MDL 100907. At 6 mo of age, the BPND in the striatum was lower in zQ175 than WT animals by 40% for 11C-raclopride, by 52% for 1F-MNI-659, by 28% for 11C-NNC, and by 11% for 11C-MDL 100907. In the rostral cortex, D1 receptor binding was 22% lower in zQ175 than WT animals. We found an overall redn. in D1 and 5-HTA binding in the hippocampus of zQ175 compared with WT animals. The BPND of 11C-MDL 100907 in the caudal cortex was also lower in zQ175 WT animals. At 9 mo, there was a slight further redn. of D1, D2, and 5-HT2A BPND in the striatum, whereas PDE10A reached a plateau. Cortical markers were also slightly further decreased at 9 mo in zQ175 animals. Our study indicates a marked redn. of ligand binding to D1 and D2 and 5-HT2A receptors as well as loss of PDE10A enzyme in the striatum of zQ175 mice as compared with WT animals, in agreement with data obtained in clin. PET studies of patients with HD. The zQ175 mouse model recapitulates the expression pattern seen in humans with HD and may have value in further elucidating pathophysiol. events and therapeutic strategies.269Cannon, D. M.; Klaver, J. M.; Peck, S. A.; Rallis-Voak, D.; Erickson, K.; Drevets, W. C. Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [11C]NNC-112. Neuropsychopharmacology 2009, 34, 1277– 1287, DOI: 10.1038/npp.2008.194[Crossref], [PubMed], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtFentLo%253D&md5=89f711aa71340c074a40933d880702abDopamine Type-1 Receptor Binding in Major Depressive Disorder Assessed Using Positron Emission Tomography and [11C]NNC-112Cannon, Dara M.; Klaver, Jacqueline M.; Peck, Summer A.; Rallis-Voak, Denise; Erickson, Kristine; Drevets, Wayne C.Neuropsychopharmacology (2009), 34 (5), 1277-1287CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clin. and preclin. evidence from neuro-imaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D1 receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [11C]NNC-112, to selectively assess D1 receptor binding in extra-striatal and striatal regions in a more generalized sample of MDD subjects. The [11C]NNC-112 nondisplaceable binding potential (BPND) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest anal. The mean D1 receptor BPND was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D1 receptor BPND in this region correlated neg. with illness duration (r=-0.53; p=0.02), and the left-to-right BPND ratio correlated inversely with anhedonia ratings (r=-0.65, p=0.0040). The D1 receptor BPND was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbent area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F=7.33, p=0.01). These data extended a previous finding of decreased striatal D1 receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathol. changes have been reported in MDD. Finally, D1 receptor binding was asym. across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior.270Martinez, D.; Slifstein, M.; Narendran, R.; Foltin, R. W.; Broft, A.; Hwang, D.-R.; Perez, A.; Abi-Dargham, A.; Fischman, M. W.; Kleber, H. D.; Laruelle, M. Dopamine D1 receptors in cocaine dependence measured with PET and the choice to self-administer cocaine. Neuropsychopharmacology 2009, 34, 1774– 1782, DOI: 10.1038/npp.2008.235[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXls12quro%253D&md5=3d6b09e40dc8fd8fc7431f581f18ba28Dopamine D1 Receptors in Cocaine Dependence Measured with PET and the Choice to Self-Administer CocaineMartinez, Diana; Slifstein, Mark; Narendran, Rajesh; Foltin, Richard W.; Broft, Allegra; Hwang, Dah-Ren; Perez, Audrey; Abi-Dargham, Anissa; Fischman, Marian W.; Kleber, Herbert D.; Laruelle, MarcNeuropsychopharmacology (2009), 34 (7), 1774-1782CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)The goal of this study was to det. D1 receptor availability in human cocaine-dependent (CD) subjects and matched healthy controls (HCs). In addn., the CD subjects performed cocaine self-administration sessions in order to explore the assocn. between D1 receptor availability and cocaine-seeking behavior. Twenty-five CD subjects (40±4 years, 19M/6 F) and 23 matched HCs (38±4 years, 19M/4F) were scanned with PET and the radiotracer [11C]NNC 112. During the cocaine self-administration sessions, CD volunteers were given the choice to self-administer cocaine (0, 6, and 12 mg) or to receive a monetary voucher worth $5. D1 receptor availability was measured in the limbic, associative, and sensori-motor striatum in addn. to cortical brain regions. No difference in D1 receptor availability was seen between the two groups. A neg. assocn. was seen between D1 receptor BPND in the limbic striatum and the choice for the 6 mg dose of cocaine (r=-0.47, p=0.02, cor. for age). These results do not support the hypothesis that cocaine dependence is assocd. with a redn. in D1 receptor availability in the striatum. However, within the CD subjects, low D1 receptor availability in the ventral striatum was assocd. with the choice to self-administer cocaine, suggesting that low D1 receptor availability may be assocd. with an increased risk of relapse in cocaine dependence. Neuropsychopharmacol. (2009) 34, 1774-1782; doi:10.1038/npp.2008.235; published online 28 Jan. 2009.271Abi-Dargham, A.; Martinez, D.; Mawlawi, O.; Simpson, N.; Hwang, D.-R.; Slifstein, M.; Anjilvel, S.; Pidcock, J.; Guo, N.-N.; Lombardo, I.; Mann, J. J.; Van Heertum, R.; Foged, C.; Halldin, C.; Laruelle, M. Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: Validation and reproducibility. J. Cereb. Blood Flow Metab. 2000, 20, 225– 243, DOI: 10.1097/00004647-200002000-00003[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhs1altbY%253D&md5=313c891d53f8ad4f704e79155444362dMeasurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in Humans: validation and reproducibilityAbi-Dargham, Anissa; Martinez, Diana; Mawlawi, Osama; Simpson, Norman; Hwang, Dah-Ren; Slifstein, Mark; Anjilvel, Satish; Pidcock, Justine; Guo, Ning-Ning; Lombardo, Ilise; Mann, J. John; Van Heertum, Ronald; Foged, Christian; Halldin, Christer; Laruelle, MarcJournal of Cerebral Blood Flow and Metabolism (2000), 20 (2), 225-243CODEN: JCBMDN; ISSN:0271-678X. (Lippincott Williams & Wilkins)To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathol. requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomog. imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of anal. (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution vol., distribution vol. ratio, binding potential (BP), and specific-to-nonspecific equil. partition coeff. (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic anal. was excellent. Time-stability anal. indicated that 90 min of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic anal. was highly reliable, with intraclass correlation coeffs. (ICCs) of 0.90 (mean of 12 regions) and 0.84, resp. The reliability of these parameters derived by graphical anal. was lower, with ICCs of 0.72 and 0.58, resp. Noise anal. revealed a noise-dependent bias in the graphical but not the kinetic anal. In conclusion, kinetic anal. of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor d.272Sedvall, G.; Karlsson, P.; Lundin, A.; Anvret, M.; Suhara, T.; Halldin, C.; Farde, L. Dopamine D1 receptor number — A sensitive PET marker for early brain degeneration in Huntington’s disease. Eur. Arch Psychiatry Clin Neurosci. 1994, 243, 249– 255, DOI: 10.1007/BF02191583[Crossref], [PubMed], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2c3islWjsQ%253D%253D&md5=2906ab08f5bc894c069fec54d0427230Dopamine D1 receptor number--a sensitive PET marker for early brain degeneration in Huntington's diseaseSedvall G; Karlsson P; Lundin A; Anvret M; Suhara T; Halldin C; Farde LEuropean archives of psychiatry and clinical neuroscience (1994), 243 (5), 249-55 ISSN:0940-1334.D1-dopamine receptor binding in the brain was determined by positron emission tomography (PET) in five patients with Huntington's disease, in one asymptomatic gene carrier and in five control subjects. [11C] SCH 23390 was used as the radioligand. Brain morphology was recorded by MRI. The patients who all had a mild to moderate functional impairment showed an almost 50% reduction of putamen volume as well as D1-dopamine receptor density as compared to the controls. The total D1-dopamine receptor number in the putamen was reduced by 75% in the patient group. A similar reduction was found for the caudate nucleus. The asymptomatic gene carrier had volume and density values in the lower range of the control subjects. In the frontal neocortex there also tended to be a reduced D1-dopamine receptor binding in the symptomatic patients. The results indicate that [11C] SCH 23390 binding in combination with MRI can be used as a sensitive marker for early brain degeneration in Huntington's disease. This marker may be useful to monitor the pathophysiological effect of the disease gene and also to follow therapeutic interventions aiming at preventing the degenerative process.273Andrews, T. C.; Weeks, R. A.; Turjanski, N.; Gunn, R. N.; Watkins, L. H. A.; Sahakian, B.; Hodges, J. R.; Rosser, A. E.; Wood, N. W.; Brooks, D. J. Huntington’s disease progression: PET and clinical observations. Brain 1999, 122, 2353– 2363, DOI: 10.1093/brain/122.12.2353[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252FltVentA%253D%253D&md5=87e3e81e581455a6887207db17dee414Huntington's disease progression. PET and clinical observationsAndrews T C; Weeks R A; Turjanski N; Gunn R N; Watkins L H; Sahakian B; Hodges J R; Rosser A E; Wood N W; Brooks D JBrain : a journal of neurology (1999), 122 ( Pt 12) (), 2353-63 ISSN:0006-8950.Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months in nine asymptomatic adult Huntington's disease mutation carriers, four patients with symptomatic disease, seven mutation-negative controls and three subjects at risk for the disease. Eight of the nine asymptomatic Huntington's disease mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of striatal D2 binding of 4.0%. Only five of these eight, however, showed active progression, and they had a mean annual loss of D2 binding of 6.5%. All nine asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated active progression and they had a mean annual loss of 4.5%. Our four symptomatic Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly greater in the known mutation carriers than in the combined at-risk and gene-negative groups (P < 0.05). At follow-up PET all subjects were clinically assessed using the Unified Huntington's Disease Rating Scale. Scores for motor function and total functional capacity correlated with PET measures of striatal dopamine receptor binding both in the asymptomatic mutation carriers (D1, P < 0.01) and across the combined asymptomatic and clinically affected Huntington's disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET measures of striatal D1 and D2 dopamine binding can be used to identify asymptomatic Huntington's disease mutation carriers who are actively progressing and who would thus be suitable for putative neuroprotective therapies. Measures of disease progression rates in Huntington's disease patients and asymptomatic mutation carriers will be of critical importance in future trials of experimental restorative treatments.274Suhara, T.; Nakayama, K.; Inoue, O.; Fukuda, H.; Shimizu, M.; Mori, A.; Tateno, Y. D1 dopamine receptor binding in mood disorders measured by positron emission tomography. Psychopharmacology. 1992, 106, 14– 18, DOI: 10.1007/BF02253582[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XisFent7w%253D&md5=922b9b183a650b8d099b99d9204907a9D1 dopamine receptor binding in mood disorders measured by positron emission tomographySuhara, Tetsuya; Nakayama, Kazuhiko; Inoue, Osamu; Fukuda, Hiroshi; Shimizu, Makoto; Mori, Atuyoshi; Tateno, YukioPsychopharmacology (Berlin, Germany) (1992), 106 (1), 14-18CODEN: PSCHDL; ISSN:0033-3158.D1 dopamine receptor binding in mood disorders was studied by positron emission tomog. (PET) using 11C-SCH23390. Ten patients with bipolar mood disorders and 21 normal controls were studied in the drug-free state. The patients were in euthymic, depressed, and manic states. Regional radioactivity in the brain was followed for 40 min by PET. A two-compartment model was used to obtain the binding potential (k3/k4) for the striatum and frontal cortex. The binding potentials for the frontal cortex for the patients were lower than those for normal controls, whereas those for striatum were not different. Thus, D1 dopamine receptors in the frontal cortex may be in a different state in patients with bipolar mood disorders.275Dougherty, D. D.; Bonab, A. A.; Ottowitz, W. E.; Livni, E.; Alpert, N. M.; Rauch, S. L.; Fava, M.; Fischman, A. J. Decreased striatal D1 binding as measured using PET and [11C]SCH 23,390 in patients with major depression with anger attacks. Depression Anxiety 2006, 23, 175– 177, DOI: 10.1002/da.20168[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvFamtLg%253D&md5=7312db60a88046a9ee320aa45eb83ab2Decreased striatal D1 binding as measured using PET and [11C]SCH 23,390 in patients with major depression with anger attacksDougherty, Darin D.; Bonab, Ali A.; Ottowitz, William E.; Livni, Eli; Alpert, Nathaniel M.; Rauch, Scott L.; Fava, Maurizio; Fischman, Alan J.Depression and Anxiety (2006), 23 (3), 175-177CODEN: DEANF5; ISSN:1091-4269. (Wiley-Liss, Inc.)This study assessed striatal dopamine 1 (D1) receptor binding in patients with major depressive disorder and anger attacks (MDD + A) and healthy volunteers. We used positron emission tomog. with [11C]SCH 23,390 to compare 10 patients with MDD + A to 10 healthy volunteers. [11C]SCH 23,390 binding in bilateral striata was significantly lower in the MDD + A group when compared to healthy volunteers. These results implicate striatal D1 receptor dysfunction in MDD + A and further suggest an assocn. between dopaminergic transmission and anger or aggression.276Farde, L.; Ehrin, E.; Eriksson, L.; Greitz, T.; Hall, H.; Hedstrom, C. G.; Litton, J. E.; Sedvall, G. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc. Natl. Acad. Sci. U. S. A. 1985, 82, 3863– 3867, DOI: 10.1073/pnas.82.11.3863[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXkvVChsb4%253D&md5=49bcdfa12ec44ea23a8672aab47dcbcdSubstituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomographyFarde, Lars; Ehrin, Erling; Eriksson, Lars; Greitz, Torgny; Hall, Haakan; Hedstroem, Carl Goeran; Litton, Jan Erik; Sedvall, GoeranProceedings of the National Academy of Sciences of the United States of America (1985), 82 (11), 3863-7CODEN: PNASA6; ISSN:0027-8424.[11C]FLB 524 (I) and [11C]raclopride (II) were prepd. and examd. for their possible use as ligands for positron emission tomog. (PET)-scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. II showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of II in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. This and previous in vitro data indicate that II binds selectively to striatal D-2 dopamine receptors. In healthy human subjects, II binding in the caudate nucleus/putamen was 4-5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, II appears to be advantageous with regard to specificity of binding to D-2 receptors, the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and rapid assocn. and reversibility of specific binding. II should be a valuable tool for characterizing D-2 receptors in the brains of patients with neuropsychiatric disorders.277Volkow, N. D.; Fowler, J. S.; Gatley, S. J.; Logan, J.; Wang, G. J.; Ding, Y. S.; Dewey, S. PET Evaluation of the dopamine system of the human brain. J. Nucl. Med. 1996, 37, 1242– 1256[PubMed], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XksF2iu74%253D&md5=9e246c1f3d0dcd420c0075b857d96984PET evaluation of the dopamine system of the human brainVolkow, Nora D.; Fowler, Joanna S.; Gatley, S. John; Logan, Jean; Wang, Gene-Jack; Ding, Yu-Shin; Dewey, StephenJournal of Nuclear Medicine (1996), 37 (7), 1242-1256CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review, with 254 refs. Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are assocd. with many neurol. and psychiatric disorders including Parkinson's disease, schizophrenia and substance abuse. This close assocn. between dopamine and neurol. and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important mol. target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compds. which have specificity for the enzymes which degrade dopamine. Addnl., by using tracers that provide information on regional brain metab. or blood flow as well as neurochem. specific pharmacol. interventions, PET can be used to assess the functional consequences of changes in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurol. diseases. It has also been used in psychopharmacol. research to investigate dopamine drugs used in the treatment of Parkinson's disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurochem. parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. Through the parallel development of new radiotracers, kinetic models and better instruments, PET technol. is enabling investigation of increasingly more complex aspects of the human brain dopamine system. This paper summarizes the different tracers and exptl. strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clin. research.278Politis, M.; Pavese, N.; Tai, Y. F.; Tabrizi, S. J.; Barker, R. A.; Piccini, P. Hypothalamic involvement in Huntington’s disease: An in vivo PET study. Brain 2008, 131, 2860– 2869, DOI: 10.1093/brain/awn244[Crossref], [PubMed], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjhs1yjsw%253D%253D&md5=67786077897c3715f5485cd0786fb2a1Hypothalamic involvement in Huntington's disease: an in vivo PET studyPolitis Marios; Pavese Nicola; Tai Yen F; Tabrizi Sarah J; Barker Roger A; Piccini PaolaBrain : a journal of neurology (2008), 131 (Pt 11), 2860-9 ISSN:.Recent studies have shown alterations in metabolism, sleep and circadian rhythms as well as in several neuropeptides derived from the hypothalamic-pituitary axis in Huntington's disease patients; however, the pathology underlying these abnormalities is not known. Our aim was to assess in vivo D(2) receptor's loss/dysfunction and increases in microglial activation in the hypothalamus of symptomatic Huntington's disease patients and premanifest Huntington's disease gene carriers using PET with (11)C-raclopride (RAC), a specific D(2) receptor ligand and (11)C-(R)-PK11195 (PK), a marker of microglial activation. We have studied 9 symptomatic Huntington's disease patients (age = 46.8 +/- 4.7 years; mean +/- SD) and 10 premanifest Huntington's disease gene carriers (age = 41.9 +/- 8.2 years; mean +/- SD). RAC and PK findings for these subjects were compared with those of a group of normal controls (RAC, n = 9; PK, n = 10). In the symptomatic Huntington's disease group, we found a significant decrease (P = 0.0012) in mean hypothalamic RAC binding potential (BP) and a significant increase in mean hypothalamic PK BP (P = 0.0008). Similarly, a significant decrease (P = 0.0143) in mean hypothalamic RAC BP and a significant increase in mean hypothalamic PK BP (P = 0.0057) were observed in the premanifest Huntington's disease group. Hypothalamic RAC and PK BP values correlated with each other in combined Huntington's disease groups (r = -0.6180, P = 0.0048) but not with striatal RAC and PK BP values. Our data demonstrate, for the first time, significant D(2) receptor loss and microglia activation in the hypothalamus of Huntington's disease. These pathological changes occur very early in the course of the disease and may partly explain the development of commonly reported symptoms in Huntington's disease including progressive weight loss, alterations in sexual behaviour and disturbances in the wake-sleep cycle.279Antonini, A.; Leenders, K. L.; Spiegel, R.; Meier, D.; Vontobel, P.; Weigell-Weber, M.; Sanchez-Pernaute, R.; de Yébenez, J. G.; Boesiger, P.; Weindl, A.; Maguire, R. P. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain 1996, 119, 2085– 2095, DOI: 10.1093/brain/119.6.2085[Crossref], [PubMed], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7mtlWktQ%253D%253D&md5=1a4959fc0a6d7f289ad1db0b26092ad1Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington's diseaseAntonini A; Leenders K L; Spiegel R; Meier D; Vontobel P; Weigell-Weber M; Sanchez-Pernaute R; de Yebenez J G; Boesiger P; Weindl A; Maguire R PBrain : a journal of neurology (1996), 119 ( Pt 6) (), 2085-95 ISSN:0006-8950.We used PET scans with the tracers [18F]fluorodeoxyglucose (FDG) and [11C]raclopride (RACLO) to study glucose metabolism and dopamine D2 receptor binding in the caudate nucleus and putamen of 18 carriers of the Huntington's disease gene mutation (10 asymptomatic subjects and eight untreated symptomatic Huntington's disease patients in an early disease stage). We also performed MRI scans and measured the bicaudate ratio (BCR) in the same subjects. Data were compared with those from nine mutation-negative members of Huntington's disease families and separate groups of age matched controls. The PET scans were repeated 1.5-3 years later in six of the asymptomatic gene carriers. Symptomatic Huntington's disease patients showed a marked reduction of FDG and RACLO uptake in the caudate nucleus and putamen and a significant increase of BCR. Asymptomatic mutation carriers revealed significant hypometabolism in the caudate nucleus and putamen. The RACLO binding was significantly decreased in the putamen. Decrements of caudate nucleus tracer uptake, particularly RACLO, correlated significantly with BCR increases in both symptomatic and asymptomatic gene carriers. In asymptomatic carriers, metabolic and receptor binding decreases were also significantly associated with the CAG repeat number but not with the individual's age. Discriminant function analysis correctly classified clinical and genetic status in 24 of 27 subjects on the basis of their striatal PET values (83% sensitivity and 100% specificity). Three asymptomatic mutation carriers were classified/grouped together with mutation-negative subjects, indicating that these individuals had normal striatal RACLO and FDG uptake. Follow-up PET data from gene-positive subjects showed a significant reduction in the mean striatal RACLO binding of 6.3% per year. Striatal glucose metabolism revealed an overall non significant 2.3% decrease per year. These data indicate that asymptomatic Huntington's disease mutation carriers may show normal neuronal function for a long period of life. These findings also suggest that it may be possible to predict when an asymptomatic gene carrier will develop clinical symptoms from serial PET measurements of striatal function.280Pavese, N.; Andrews, T. C.; Brooks, D. J.; Ho, A. K.; Rosser, A. E.; Barker, R. A.; Robbins, T. W.; Sahakian, B. J.; Dunnett, S. B.; Piccini, P. Progressive striatal and cortical dopamine receptor dysfunction in Huntington’s disease: A PET study. Brain 2003, 126, 1127– 1135, DOI: 10.1093/brain/awg119[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7ntVylsg%253D%253D&md5=17daaaea7f6b647540f27331f9118e09Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET studyPavese Nicola; Andrews Thomasin C; Brooks David J; Ho Aileen K; Rosser Anne E; Barker Roger A; Robbins Trevor W; Sahakian Barbara J; Dunnett Stephen B; Piccini PaolaBrain : a journal of neurology (2003), 126 (Pt 5), 1127-35 ISSN:0006-8950.We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.281Tang, C. C.; Feigin, A.; Ma, Y.; Habeck, C.; Paulsen, J. S.; Leenders, K. L.; Teune, L. K.; van Oostrom, J. C. H.; Guttman, M.; Dhawan, V.; Eidelberg, D. Metabolic network as a progression biomarker of premanifest Huntington’s disease. J. Clin. Invest. 2013, 123, 4076– 4088, DOI: 10.1172/JCI69411[Crossref], [PubMed], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVemsrzK&md5=5e6229eb7e38ba606f0317985acd415cMetabolic network as a progression biomarker of premanifest Huntington's diseaseTang, Chris C.; Feigin, Andrew; Ma, Yilong; Habeck, Christian; Paulsen, Jane S.; Leenders, Klaus L.; Teune, Laura K.; van Oostrom, Joost C. H.; Guttman, Mark; Dhawan, Vijay; Eidelberg, DavidJournal of Clinical Investigation (2013), 123 (9), 4076-4088CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)Background: The evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network assocd. with the progression of preclin. Huntington's disease (HD). Methods: Twelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue vol. The rate of metabolic network progression in this cohort was compared with the corresponding est. obtained in a sep. group of 21 premanifest HD carriers who were scanned twice over a 2-yr period. Results: In the original premanifest cohort, network anal. disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approx. twice the rate of single region measurements from the same subjects. Conclusion: Metabolic network measurements provide a sensitive means of quant. evaluating disease progression in premanifest individuals. This approach may be incorporated into clin. trials to assess disease-modifying agents.282van Oostrom, J. C. H.; Maguire, R. P.; Verschuuren-Bemelmans, C. C.; Veenma-Van der Duin, L.; Pruim, J.; Roos, R. A. C.; Leenders, K. L. Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease. Neurology 2005, 65, 941– 943, DOI: 10.1212/01.wnl.0000176071.08694.cc[Crossref], [PubMed], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpslyksrc%253D&md5=32f3275fdac80512d466a0a149fb4ea1Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington diseasevan Oostrom, J. C. H.; Maguire, R. P.; Verschuuren-Bemelmans, C. C.; Veenma-van der Duin, L.; Pruim, J.; Roos, R. A. C.; Leenders, K. L.Neurology (2005), 65 (6), 941-943CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Among 27 preclin. carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the product of age and CAG repeat length (p < 0.0005). Dopamine D2 receptor availability measured by RAC-BP seems the most sensitive indicator of early neuronal impairment in PMC.283Antonini, A.; Leenders, K. L.; Eidelberg, D. [11C]raclopride-PET studies of the Huntington’s disease rate of progression: relevance of the trinucleotide repeat length. Ann. Neurol. 1998, 43, 253– 255, DOI: 10.1002/ana.410430216[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1c7ktlKjsw%253D%253D&md5=2c04602444e09df172245550a93585ef11C]raclopride-PET studies of the Huntington's disease rate of progression: relevance of the trinucleotide repeat lengthAntonini A; Leenders K L; Eidelberg DAnnals of neurology (1998), 43 (2), 253-5 ISSN:0364-5134.We used [11C]raclopride and positron emission tomography (PET) to assess the relationship between striatal dopamine D2 receptor binding, trinucleotide repeat number (CAG), and subject age in 10 asymptomatic and 8 symptomatic carriers of the Huntington's disease (HD) mutation. In both preclinical and symptomatic gene carriers, we found significant correlations between CAG repeat length and the ratio of percent loss in striatal D2 receptor binding divided by age. In accord with neuropathological studies, we obtained an intercept at 35.5 CAG repeats in the symptomatic HD patients. Nonetheless, we noted that the slopes of the correlation lines differed significantly for the presymptomatic and symptomatic cohorts. These PET results support the notion that the HD disease process is a function of trinucleotide length and age, and that the development of clinical signs and symptoms is associated with CAG repeat lengths greater than 35.5. However, our analysis also suggests that striatal degeneration may proceed in a nonlinear fashion. These findings have implications for the design of neuroprotective strategies for the treatment of HD.284Pavese, N.; Politis, M.; Tai, Y. F.; Barker, R. A.; Tabrizi, S. J.; Mason, S. L.; Brooks, D. J.; Piccini, P. Cortical dopamine dysfunction in symptomatic and premanifest Huntington’s disease gene carriers. Neurobiol. Dis. 2010, 37, 356– 361, DOI: 10.1016/j.nbd.2009.10.015[Crossref], [PubMed], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXos1Cl&md5=2fa3582d26f14134e23fc1085dbfaf4eCortical dopamine dysfunction in symptomatic and premanifest Huntington's disease gene carriersPavese, Nicola; Politis, Marios; Tai, Yen F.; Barker, Roger A.; Tabrizi, Sarah J.; Mason, Sarah L.; Brooks, David J.; Piccini, PaolaNeurobiology of Disease (2010), 37 (2), 356-361CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)We used 11C-raclopride PET, a marker of D2 dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D2 receptor dysfunction in individual Huntington's disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clin. significance. 62.5% Of symptomatic HD patients and 54.5% of premanifest carriers showed cortical redns. in D2 binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D2 binding had worse scores on neuropsychol. tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable redn. in striatal D2 binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiol. and could contribute to the impairment in neuropsychol. performance in these patients.285Esmaeilzadeh, M.; Farde, L.; Karlsson, P.; Varrone, A.; Halldin, C.; Waters, S.; Tedroff, J. Extrastriatal dopamine D2 receptor binding in Huntington’s disease. Hum. Brain Mapp. 2011, 32, 1626– 1636, DOI: 10.1002/hbm.21134[Crossref], [PubMed], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MfitVKqsQ%253D%253D&md5=defaf31f9ecfacee241cfc3ab7ed3d19Extrastriatal dopamine D(2) receptor binding in Huntington's diseaseEsmaeilzadeh Mouna; Farde Lars; Karlsson Per; Varrone Andrea; Halldin Christer; Waters Susanna; Tedroff JoakimHuman brain mapping (2011), 32 (10), 1626-36 ISSN:.Huntington's disease (HD) is a neurodegenerative disorder, primarily affecting medium spiny neurones in the striatum. The density of striatal dopamine D(2) receptors is reduced in HD but there is little known about this biomarker in brain regions outside the striatum. The primary objective of this study was to compare extrastriatal dopamine D(2) receptor binding, in age-matched control subjects and patients with HD. All subjects were examined using a high-resolution positron emission tomography system and the high-affinity dopamine D(2) receptor radioligand [(11) C]FLB 457. A ROI based analysis was used with an atrophy correction method. Dopamine D(2) receptor binding potential was reduced in the striatum of patients with HD. Unlike the striatum, dopamine D(2) receptor binding in thalamic and cortical subregions was not significantly different from that in control subjects. A partial least square regression analysis which included binding potential values from all investigated cortical and subcortical regions revealed a significant model separating patients from controls, conclusively dependent on differences in striatal binding of the radioligand. Some clinical assessments correlated with striatal dopamine D(2) receptor binding, including severity of chorea and cognitive test performance. Hence, the present study demonstrates that dopamine D(2) receptors extrinsic to the striatum are well preserved in early to mid stage patients with HD. This observation may have implication for the development of therapy for HD.286Volkow, N. D.; Wang, G.-J.; Fowler, J. S.; Thanos, P.; Logan, J.; Gatley, S. J.; Gifford, A.; Ding, Y.-S.; Wong, C.; Pappas, N. Brain DA D2 receptors predict reinforcing effects of stimulants in humans: Replication study. Synapse 2002, 46, 79– 82, DOI: 10.1002/syn.10137[Crossref], [PubMed], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XnvFKit7o%253D&md5=e8874419f52619355da2d9991915141dBrain DA D2 receptors predict reinforcing effects of stimulants in humans: replication studyVolkow, Nora D.; Wang, Gene-Jack; Fowler, Joanna S.; Thanos, Pether; Logan, Jean; Gatley, Samuel J.; Gifford, Andrew; Ding, Yu-Shin; Wong, Chris; Pappas, NaomiSynapse (New York, NY, United States) (2002), 46 (2), 79-82CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)We had shown that striatal DA D2 receptors levels predicted the reinforcing responses to the psychostimulant drug methylphenidate in nondrug-abusing subjects. Here, we assessed the replicability of this finding. We measured D2 receptors with PET and [11C]raclopride (twice to det. stability) in seven nondrug-abusing subjects to assess if they predicted the self-reports of "drug-liking" to i.v. methylphenidate (0.5 mg/kg). DA D2 measures were significantly correlated with "drug-liking" in both evaluations (r = 0.82 and r = 0.78); subjects with the lowest levels reported the higher ratings of "drug-liking" and vice versa. These results replicate our previous findings and provide further evidence that striatal DA D2 receptors modulate reinforcing responses to stimulants in humans and may underlie predisposition for drug self-administration.287Volkow, N. D.; Wang, G.-J.; Begleiter, H.; Porjesz, B.; Fowler, J. S.; Telang, F.; Wong, C.; Ma, Y.; Logan, J.; Goldstein, R.; Alexoff, D.; Thanos, P. K. High levels of dopamine D2 receptors in unaffected members of alcoholic families: Possible protective factors. Arch. Gen. Psychiatry 2006, 63, 999– 1008, DOI: 10.1001/archpsyc.63.9.999[Crossref], [PubMed], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVamtr7I&md5=c25bb3df43eb333ceca2bc75293529ffHigh levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factorsVolkow, Nora D.; Wang, Gene-Jack; Begleiter, Henri; Porjesz, Bernice; Fowler, Joanna S.; Telang, Frank; Wong, Christopher; Ma, Yeming; Logan, Jean; Goldstein, Rita; Alexoff, David; Thanos, Peter K.Archives of General Psychiatry (2006), 63 (9), 999-1008CODEN: ARGPAQ; ISSN:0003-990X. (American Medical Association)Context: Predisposition to alcoholism is likely an interaction between genetic and environmental factors that confer vulnerability and protection. Alc. subjects have low levels of dopamine D2 receptors in striatum, and increasing D2 receptor levels in lab. animals reduces alc. consumption. Objectives: To test whether high levels of D2 receptors may be protective against alcoholism and whether this is mediated by their modulation of activity in orbitofrontal cortex and cingulate gyrus (regions involved in salience attribution, emotional reactivity, and inhibitory control). Design: Research (nonalcoholic subjects with a family history of alcoholism) and comparison (nonalcoholic subjects with a neg. family history) sample. Setting: Outpatient setting. Participants: Fifteen nonalcoholic subjects who had an alc. father and at least 2 other first- or second-degree relatives who were alcoholics (family-pos. group) and 16 nonalcoholic controls with no family history of alcoholism (family-neg. group). Main Outcome Measures: Results of positron emission tomog. with raclopride C 11 to assess D2 receptors and with fludeoxyglucose F 18 to assess brain glucose metab. (marker of brain function). Personality measures were obtained with the Multidimensional Personality Questionnaire. Results: Availability of D2 receptors was significantly higher in caudate and ventral striatum in family-pos. than family-neg. subjects. In family-pos. but not family-neg. subjects, striatal D2 receptors were assocd. with metab. in anterior cingulate (Brodmann area 24/25) and orbitofrontal (Brodmann area 11) and prefrontal (Brodmann area 9/10) cortices, and with personality scores of pos. emotionality. Conclusions: The higher-than-normal D2 receptor availability in nonalcoholic members of alc. families supports the hypothesis that high levels of D2 receptors may protect against alcoholism. The significant assocns. between D2 receptors and metab. in frontal regions involved with emotional reactivity and executive control suggest that high levels of D2 receptors could protect against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions.288Olsson, H.; Halldin, C.; Farde, L. Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. NeuroImage 2004, 22, 794– 803, DOI: 10.1016/j.neuroimage.2004.02.002[Crossref], [PubMed], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c3ptlKqtw%253D%253D&md5=040da3cddfdfa39f476eff4d7aa8b2c3Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PETOlsson Hans; Halldin Christer; Farde LarsNeuroImage (2004), 22 (2), 794-803 ISSN:1053-8119.Dopaminergic neurotransmission in extrastriatal regions may play a crucial role in the pathophysiology and treatment of neuropsychiatric disorders. The high-affinity radioligands [(11)C]FLB 457, [(123)I]epidepride, and [(18)F]fallypride are now used in clinical studies to measure these low-density receptor populations in vivo. However, a single determination of the regional binding potential (BP) does not differentiate receptor density (B(max)) from the apparent affinity (K(D)). In this positron emission tomography (PET) study, we measured extrastriatal dopamine D2 receptor density (B(max)) and apparent affinity (K(D)) in 10 healthy subjects using an in vivo saturation approach. Each subject participated in two to three PET measurements with different specific radioactivity of [(11)C]FLB 457. The commonly used simplified reference tissue model (SRTM) was used in a comparison of BP values with the B(max) values obtained from the saturation analysis. The calculated regional receptor density values were of the same magnitude (0.33-1.68 nM) and showed the same rank order as reported from postmortem studies, that is, in descending order thalamus, lateral temporal cortex, anterior cinguli, and frontal cortex. The affinity ranged from 0.27 to 0.43 nM, that is, approximately 10-20 times the value found in vitro (20 pM). The area under the cerebellar time activity curve (TAC) was slightly lower (11 +/- 8%, mean +/- SD, P = 0.004, n = 10) after injection of low as compared with high specific radioactivity, indicating sensitivity to the minute density of dopamine D2 receptors in the this region. The results of the present study support that dopamine D2 receptor density and affinity can be differentiated in low-density regions using a saturation approach. There was a significant (P < 0.001) correlation between the binding potential calculated with SRTM and the receptor density (B(max)), which supports the use of BP in clinical studies where differentiation of B(max) and K(D) is not required. In such studies, the mass of FLB 457 has to be less than 0.5 microg injected to avoid a mass effect of the radioligand itself.289Sudo, Y.; Suhara, T.; Inoue, M.; Ito, H.; Suzuki, K.; Saijo, T.; Halldin, C.; Farde, L. Reproducibility of [11C]FLB 457 binding in extrastriatal regions. Nucl. Med. Commun. 2001, 22, 1215– 1221, DOI: 10.1097/00006231-200111000-00008[Crossref], [PubMed], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXoslSrtLs%253D&md5=3a17b24e65c8e0b06f59fb57d14b5b6eReproducibility of [11C]FLB 457 binding in extrastriatal regionsSudo, Y.; Suhara, T.; Inoue, M.; Ito, H.; Suzuki, K.; Saijo, T.; Halldin, C.; Farde, L.Nuclear Medicine Communications (2001), 22 (11), 1215-1221CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)Extrastriatal D2 dopamine receptors represent an important target of research into the pathophysiol. and pharmacotherapy of psychiatric disorders. The high affinity radioligand [11C]FLB 457 makes possible the measurement of low concns. of D2 receptors in extrastriatal regions using positron emission tomog. (PET). The aim of this study was to assess the test/retest variability and reliability of [11C]FLB 457 binding using a ref. tissue model. Eight healthy male subjects (aged 20-33 yr) underwent two [11C]FLB 457 PET examns. Radioactivity in the cerebellum was used as the ref. The binding potentials (BPs) for five cortical regions of interest (ROIs) were calcd. using the ref. tissue model. The BP was also calcd. for each pixel in the form of parametric images. Reproducibility was assessed both for the ROI method and for the parametric images. The test/retest reproducibility for [11C]FLB 457 binding was good, with a mean variability ranging from 4.5% for the thalamus to 15.5% for the hippocampus. The parametric images also demonstrated good reproducibility. These results support the suitability of using [11C]FLB 457 for the quant. evaluation of extrastriatal D2 receptors and for protocols requiring repeated measurements in the same individual.290Suhara, T.; Sudo, Y.; Okauchi, T.; Maeda, J.; Kawabe, K.; Suzuki, K.; Okubo, Y.; Nakashima, Y.; Ito, H.; Tanada, S.; Halldin, C.; Farde, L. Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET. Int. J. Neuropsychopharmacol. 1999, 2, 73– 82, DOI: 10.1017/S1461145799001431[Crossref], [PubMed], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXlvVans7c%253D&md5=cf8b85307fdcb46720785001d21b1e03Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PETSuhara, Tetsuya; Sudo, Yasuhiko; Okauchi, Takashi; Maeda, Jun; Kawabe, Koichi; Suzuki, Kazutoshi; Okubo, Yoshiro; Nakashima, Yoshifumi; Ito, Hiroshi; Tanada, Shuji; Halldin, Christer; Farde, LarsInternational Journal of Neuropsychopharmacology (1999), 2 (2), 73-82CODEN: IJNUFB; ISSN:1461-1457. (Cambridge University Press)The aim of the present study was to quantify the d. and affinity of human extrastriatal dopamine D2 receptors using positron emission tomog. (PET). [11C]FLB-457, a high-affinity dopamine D2 receptor antagonist with various specific radioactivities (SA) was used. Eight healthy male subjects, age 20-35 yr, participated twice or three times at different SAs (1-279 GBq/μmol), and serial dynamic scans were performed in the 3D data acquisition mode. The peak of the specific binding was not well defined with high SA due to the flatness of the curves after 60 min but was obsd. within the PET measurement. In the expt. with low SA, the peak came earlier than that with high SA. Scatchard anal. was performed using the maximal specific binding value (transient equil.) and the radioactivity in the cerebellum as free ligand concn. The highest d. was obsd. in the thalamus (2.3 ± 0.6 pmol/mL), followed by the temporal cortex (1.5 ± 0.5 pmol/mL), hippocampus (1.4 ± 0.5 pmol/mL), parietal cortex (0.9 ± 0.4 pmol/mL), frontal cortex (0.8 ± 0.2 pmol/mL) and occipital cortex (0.7 ± 0.3 pmol/mL). There was no significant difference in Kd values in these six regions. The present results demonstrate that dopamine D2 receptor densities in the extrastriatal regions were only 2-8% of that in the striatum. Although the d. of extrastriatal dopamine D2 receptor was low, significant regional differences were obsd. in the present study, as reported in postmortem studies.291Vilkman, H.; Kajander, J.; Någren, K.; Oikonen, V.; Syvälahti, E.; Hietala, J. Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457 - A test-retest analysis. Eur. J. Nucl. Med. Mol. Imaging 2000, 27, 1666– 1673, DOI: 10.1007/s002590000342292Montgomery, A. J.; Stokes, P.; Kitamura, Y.; Grasby, P. M. Extrastriatal D2 and striatal D2 receptors in depressive illness: Pilot PET studies using [11C]FLB 457 and [11C]raclopride. J. Affective Disord. 2007, 101, 113– 122, DOI: 10.1016/j.jad.2006.11.010[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtlSntrc%253D&md5=db5998e35ab4b48889fe732cdfdb6527Extrastriatal D2 and striatal D2 receptors in depressive illness: Pilot PET studies using [11C]FLB 457 and [11C]racloprideMontgomery, Andrew J.; Stokes, Paul; Kitamura, Yuri; Grasby, Paul M.Journal of Affective Disorders (2007), 101 (1-3), 113-122CODEN: JADID7; ISSN:0165-0327. (Elsevier Ltd.)Reduced dopaminergic function may occur in depressive disorders. In this paper the results of two pilot studies examg. different aspects of the dopamine system in depression are presented. First, the binding of [11C]FLB 457 to extrastriatal D2 receptors was measured in a group of depressed patients. Second, the hypothesis that selective serotonin reuptake inhibiting (SSRI) antidepressants affect the striatal binding of [11C]raclopride was tested. In the first study the binding of [11C]FLB 457 was compared between 7 people with depression and 7 healthy controls. In the second study the binding of [11C]raclopride to striatal D2/3 receptors was compared between 8 people taking SSRI antidepressant medication and 8 healthy controls. There was no difference in the binding of [11C]FLB 457 between the two groups. [11C]raclopride binding was reduced in the dorsal striatum of people taking antidepressants suggesting either that D2/3 expression was reduced, or that dopamine release was increased, compared to untreated controls. The depressed patients were not severely depressed and were not matched for gender with controls. In the raclopride group the patients and controls were not matched by gender and were taking different SSRI antidepressants. We found no support for the hypothesis that dopamine D2 receptor expression is altered in extrastriatal brain regions in depression. SSRI antidepressants were assocd. with reduced [11C]raclopride binding in the dorsal striatum supporting the hypothesis that therapeutic effects of such drugs may, in part, be due to changes in the dopamine system.293Saijo, T.; Takano, A.; Suhara, T.; Arakawa, R.; Okumura, M.; Ichimiya, T.; Ito, H.; Okubo, Y. Electroconvulsive therapy decreases dopamine D2 receptor binding in the anterior cingulate in patients with depression: A controlled study using positron emission tomography with radioligand [11C]FLB 457. J. Clin. Psychiatry 2010, 71, 793– 799, DOI: 10.4088/JCP.08m04746blu[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3crovVGltw%253D%253D&md5=a9693e60a6bf0e7c9b2c9a32b2616d29Electroconvulsive therapy decreases dopamine D2receptor binding in the anterior cingulate in patients with depression: a controlled study using positron emission tomography with radioligand [11C]FLB 457Saijo Tomoyuki; Takano Akihiro; Suhara Tetsuya; Arakawa Ryosuke; Okumura Masaki; Ichimiya Tetsuya; Ito Hiroshi; Okubo YoshiroThe Journal of clinical psychiatry (2010), 71 (6), 793-9 ISSN:.OBJECTIVE: Electroconvulsive therapy (ECT) has been confirmed as one of the most effective treatments in drug-resistant major depression. However, the mechanism of ECT is still poorly understood. Although several lines of studies have focused on its effect on dopamine neurotransmission, the effects of ECT on dopamine D(2) receptors in a living human brain have not been investigated. Using positron emission tomography (PET) scans with the radioligand [(11)C]FLB 457, we aimed to evaluate the effect of ECT on extrastriatal D(2) receptor binding in medicated patients with major depressive disorder (MDD). METHOD: Seven patients with a DSM-IV diagnosis of MDD underwent PET scans before and after a series of 6-7 treatments with bilateral ECT. Eleven healthy controls were scanned for comparison. All participants were scanned at the National Institute of Radiological Sciences, Chiba, Japan, between November 2000 and September 2005. The parametric images of [(11)C]FLB 457 binding were generated on the basis of a simplified reference tissue model. Voxel-based methods were used to assess the effect of ECT on D(2) receptor binding. RESULTS: There were no significant differences in D(2) receptor binding between patients with MDD and controls. All 7 patients showed clinical improvements in response to ECT treatment (P < .001). Significant changes in D(2) receptor binding, a mean of 25.2% reduction, were found in the right rostral anterior cingulate (AC) following ECT (P < .001). CONCLUSIONS: Electroconvulsive therapy decreased D(2) receptor binding in the rostral AC in MDD patients responding to ECT. Our finding suggests that one of the biologic mechanisms of ECT could be related to dopaminergic alteration in the rostral AC.294Turjanski, N.; Weeks, R.; Dolan, R.; Harding, A. E.; Brooks, D. J. Striatal D1 and D2 receptor binding in patients with Huntington’s disease and other choreas A PET study. Brain 1995, 118, 689– 696, DOI: 10.1093/brain/118.3.689[Crossref], [PubMed], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2MzitlCnug%253D%253D&md5=f3d6c0346ed8a7a88757aecdfeb78402Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET studyTurjanski N; Weeks R; Dolan R; Harding A E; Brooks D JBrain : a journal of neurology (1995), 118 ( Pt 3) (), 689-96 ISSN:0006-8950.We have used PET to study striatal D1 and D2 receptor binding in 10 patients with either the choreic or akinetic-rigid variants of Huntington's disease and in three patients with other causes of chorea. Background rigidity and bradykinesia in choreic patients were scored with a four-point scale. PET studies showed a severe and parallel reduction of both striatal D1 and D2 receptor binding in Huntington's disease patients irrespective of their predominant phenotype (mean reduction 60%). Huntington's disease patients with rigidity showed more pronounced reduction of striatal D1 and D2 binding compared with those without rigidity. A case of chorea associated with systemic lupus erythematosus had normal D2 binding. These results suggest that the presence of chorea per se may not be determined by alterations in striatal dopamine receptor binding, but that rigidity in Huntington's disease is associated with severe striatal D1 and D2 receptor loss.295Pearlson, G. D. In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder. Arch. Gen. Psychiatry 1995, 52, 471– 477, DOI: 10.1001/archpsyc.1995.03950180057008[Crossref], [PubMed], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2M3ovFylsQ%253D%253D&md5=5316e84108e2af3ad2c9c20fcd1c9e2fIn vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorderPearlson G D; Wong D F; Tune L E; Ross C A; Chase G A; Links J M; Dannals R F; Wilson A A; Ravert H T; Wagner H N JrArchives of general psychiatry (1995), 52 (6), 471-7 ISSN:0003-990X.BACKGROUND: A prior positron emission tomographic study from The Johns Hopkins University, Baltimore, Md, using N-methylspiperone labeled with carbon 11 reported elevated basal ganglia D2 dopamine receptor density (Bmax) values in neuroleptic-naive schizophrenic patients compared with controls. We have now extended these studies to include patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 14) either had never received neuroleptic medication or had been neuroleptic-free for more than 6 months, and they met DSM-III criteria for currently symptomatic affective disorder. Patients with bipolar disorder were compared with matched schizophrenic patients and normal controls. All received two positron emission tomographic scans, the second of which was preceded by oral administration of haloperidol lactate, to permit the calculation of D2 dopamine receptor Bmax. RESULTS: Diagnostic groups differed in Bmax by analysis of variance (P < .0001); post hoc tests showed higher Bmax values for psychotic patients with bipolar disorder and schizophrenic patients compared with normal controls and for schizophrenic patients and psychotic patients with bipolar disorder compared with nonpsychotic patients with bipolar disorder. Among patients with bipolar disorder, Bmax values correlated significantly with the severity of psychotic symptoms (r = .63) on the Present State Examination but not with the severity of nonpsychotic mood symptoms. CONCLUSIONS: We conclude that, like schizophrenic patients, patients with psychotic bipolar disorder have elevations of D2 dopamine receptor Bmax values and that such elevations in affective disorder are more closely associated with the presence of psychosis than with mood abnormality. Elevations in dopamine receptor values thus may occur in psychiatric states that are characterized by psychotic symptoms rather than being specific to schizophrenia.296Wong, D. F.; Pearlson, G. D.; Tune, L. E.; Young, L. T.; Meltzer, C. C.; Dannals, R. F.; Ravert, H. T.; Reith, J.; Kuhar, M. J.; Gjedde, A. Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness. J. Cereb. Blood Flow Metab. 1997, 17, 331– 342, DOI: 10.1097/00004647-199703000-00010[Crossref], [PubMed], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3ktlCmsg%253D%253D&md5=c51468ca6ffe327c1d58cd27fc62741eQuantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illnessWong D F; Pearlson G D; Tune L E; Young L T; Meltzer C C; Dannals R F; Ravert H T; Reith J; Kuhar M J; Gjedde AJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (1997), 17 (3), 331-42 ISSN:0271-678X.In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C]methyl-spiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.297Brooks, D. J. Imaging approaches to Parkinson disease. J. Nucl. Med. 2010, 51, 596– 609, DOI: 10.2967/jnumed.108.059998[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXls12guro%253D&md5=9e3aadb751395e2d59574b11d52e924eImaging approaches to Parkinson diseaseBrooks, David J.Journal of Nuclear Medicine (2010), 51 (4), 596-609CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review. Parkinson disease (PD) is assocd. with nigral degeneration and striatal dopamine deficiency. Demonstrating midbrain structural abnormalities with transcranial sonog. or diffusion-weighted MRI or showing striatal dopamine terminal dysfunction with PET or SPECT supports the diagnosis and rationalizes the use of dopaminergic medications. In atypical PD variants, transcranial sonog. can detect striatal hyperechogenicity, and diffusion-weighted imaging can detect increased putamen water diffusion, whereas 18F-FDG PET reveals reduced lentiform nucleus glucose metab. PET and SPECT can detect changes in striatal dopamine levels after levodopa administration and relate these to motor responses. Loss of cortical dopaminergic and cholinergic function is present in demented PD and, on occasion, amyloid deposits can be detected. Loss of cardiac sympathetic innervation can be sensitively detected in PD with 18F-dopamine PET or 123I-metaiodobenzylguanidine SPECT. Finally, PET can detect widespread brain inflammation in PD. This review discusses the role of structural and functional imaging for diagnosing and managing different parkinsonian syndromes.298Brooks, D. J.; Ibanez, V.; Sawle, G. V.; Playford, E. D.; Quinn, N.; Mathias, C. J.; Lees, A. J.; Marsden, C. D.; Bannister, R.; Frackowiak, R. S. J. Striatal D2 receptor status in patients with Parkinson’s disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann. Neurol. 1992, 31, 184– 192, DOI: 10.1002/ana.410310209[Crossref], [PubMed], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK383ks1ClsQ%253D%253D&md5=3eba2f143bab790eef32cf542d4dac06Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomographyBrooks D J; Ibanez V; Sawle G V; Playford E D; Quinn N; Mathias C J; Lees A J; Marsden C D; Bannister R; Frackowiak R SAnnals of neurology (1992), 31 (2), 184-92 ISSN:0364-5134.Equilibrium striatal: cerebellar 11C-raclopride (RAC) uptake ratios reflect the density of striatal dopamine D2 binding sites. Using positron emission tomographic scanning we have measured striatal RAC uptake in 6 untreated patients with Parkinson's disease (PD), 5 chronically treated patients with PD and a fluctuating response to L-dopa, 10 patients with striatonigral degeneration (SND), and 9 patients with progressive supranuclear palsy (PSP). Regional cerebral blood flow was determined also, with C15O2. Mean striatal: cerebellar RAC uptake was not significantly different from normal in untreated patients with PD, though 2 of these 6 patients showed significantly increased putamen tracer binding. Mean caudate and putamen: cerebellar RAC uptake ratios of the group with PD and a fluctuating response to L-dopa were significantly reduced by 30% and 18%, respectively. The patients with SND had lesser, but significant, 10% and 11% decreases in mean caudate and putamen: cerebellar RAC uptake ratios, respectively, whereas patients with PSP showed 24% and 9% reductions in caudate and putamen: cerebellar RAC binding. Striatal and frontal blood flow were significantly reduced in patients with PSP, but not in patients with PD or SND. In conclusion, striatal D2 binding potential is normal or raised in untreated patients with PD, but reduced in patients with PD and a fluctuating response to L-dopa. Patients with SND and PSP show a decrease in striatal RAC binding, but to a lesser extent than patients with PD and a fluctuating response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)299Antonini, A.; Schwarz, J.; Oertel, W. H.; Beer, H. F.; Madeja, U. D.; Leenders, K. L. [11C]Raclopride and positron emission tomography in previously untreated patients with Parkinson’s disease: Influence of L-dopa and lisuride therapy on striatal dopamine D2-receptors. Neurology 1994, 44, 1325– 1325, DOI: 10.1212/WNL.44.7.1325[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2czgvFyhsg%253D%253D&md5=89a69320fa0bfe8776211a5e6431d42a11C]raclopride and positron emission tomography in previously untreated patients with Parkinson's disease: Influence of L-dopa and lisuride therapy on striatal dopamine D2-receptorsAntonini A; Schwarz J; Oertel W H; Beer H F; Madeja U D; Leenders K LNeurology (1994), 44 (7), 1325-9 ISSN:0028-3878.We studied cerebral dopamine D2-receptor binding using [11C]raclopride and PET in 18 previously untreated patients with Parkinson's disease (PD) and 14 healthy volunteer subjects. Sixteen patients were scanned before and after 3 to 4 months of stable oral therapy with either L-dopa (300 mg/d) (n = 7) or lisuride (0.8 to 1.2 mg/d) (n = 9). Two additional patients were investigated before and after a continuous IV infusion of L-dopa. In addition, we studied the effect of acute IV L-dopa and lisuride administration on [11C]raclopride binding in a healthy rhesus monkey. At baseline, PD patients showed higher uptake values in the putamen than did healthy subjects (p < 0.0001). Oral lisuride treatment lowered [11C]raclopride uptake in the putamen (-19%) and in the caudate nucleus (-15%) compared with baseline, but the difference did not reach significance upon Bonferroni correction for multiple comparisons. However, putamen tracer uptake returned to baseline in two patients when we repeated [11C]raclopride scans 4 days after lisuride withdrawal. Oral L-dopa treatment did not induce changes in the putamen or caudate nucleus indices. Acute lisuride (25 micrograms) administration in a healthy monkey reduced striatal uptake values, but acute injection of L-dopa (300 mg) did not. The results suggest that lisuride blocks [11C]raclopride binding at dopamine D2-receptor sites and demonstrate that 3 to 4 months' oral therapy with L-dopa or lisuride does not change striatal dopamine D2-receptor density in PD patients.300Antonini, A.; Schwarz, J.; Oertel, W. H.; Pogarell, O.; Leenders, K. L. Long-term changes of striatal dopamine D2 Receptors in patients with Parkinson’s disease: A study with positron emission tomography and [11C]raclopride. Mov. Disord. 1997, 12, 33– 38, DOI: 10.1002/mds.870120107[Crossref], [PubMed], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7ksVahtw%253D%253D&md5=b412f5b912793aec2645ad8c6aa92756Long-term changes of striatal dopamine D2 receptors in patients with Parkinson's disease: a study with positron emission tomography and [11C]racloprideAntonini A; Schwarz J; Oertel W H; Pogarell O; Leenders K LMovement disorders : official journal of the Movement Disorder Society (1997), 12 (1), 33-8 ISSN:0885-3185.We used [11C]raclopride (RACLO) and positron emission tomography (PET) to study longitudinally striatal dopamine D2 receptor binding in nine patients with Parkinson's disease (PD) at an early drug-naive stage and 3-5 years later, when motor fluctuations had appeared in seven of them. Patients were treated with a combination of levodopa and dopamine agonists. Data were compared with 10 healthy controls in the same age range. Initially, patients with PD showed a significant increase of RACLO uptake in the putamen compared with controls (p < 0.04). The caudate nucleus revealed values in the normal range. After 3-5 years, RACLO binding was significantly reduced in the putamen (p < 0.03) and caudate nucleus (p < 0.03) compared with baseline. Values were now in the control range in the putamen and reduced in the caudate nucleus (p < 0.05). The clinical score at "off" had significantly worsened (p < 0.0005) compared with the first PET scan. The nine PD patients reported here had already been investigated 3-4 months after therapy began and that time did not show a reduction of the initially increased RACLO binding capacity (data published previously). These results indicate long-term downregulation of striatal dopamine D2 receptor binding in PD. Receptor changes in the striatum of patients with PD may be induced by chronic dopaminergic therapy or occur independently of treatment, as a result of structural adaptation of the postsynaptic dopaminergic system to the progressive decline of nigrostriatal neurons.301Rinne, J. O.; Laihinen, A.; Ruottinen, H.; Ruotsalainen, U.; Någren, K.; Lehikoinen, P.; Oikonen, V.; Rinne, U. K. Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson’s disease: A PET study with [11C]raclopride. J. Neurol. Sci. 1995, 132, 156– 161, DOI: 10.1016/0022-510X(95)00137-Q[Crossref], [PubMed], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXptlWqtb0%253D&md5=009715926a74d89c62ad1bcc8bd99bf6Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease: A PET study with [11C]racloprideRinne, Juha O.; Laihinen, Arto; Ruottinen, Hanna; Ruotsalainen, Ulla; Nagren, Kjell; Pertti, Lehikoinen; Oikonen, Vesa; Rinne, U. K.Journal of the Neurological Sciences (1995), 132 (2), 156-61CODEN: JNSCAG; ISSN:0022-510X. (Elsevier)Striatal dopamine D2 receptors were studied, using positron emission tomog. (PET), in 10 patients with early Parkinson's disease without any antiparkinsonian medication and in 14 healthy controls. [11C]Raclopride was used as ligand and an equil. method was applied. The max. count of receptors (Bmax) and their dissocn. const. (Kd) were calcd. according to the Scatchard principle. In parkinsonian patients, the Bmax of D2 receptors was increased in the putamen contralateral to the predominant symptoms, as compared to the opposite putamen, by 33% (p = 0.0008). In the caudate nucleus no significant side to side differences was noted. On comparison with age-matched healthy controls, Bmax values in the putamen (p = 0.0012) but not in the caudate nucleus contralateral to the side of predominant clin. symptoms were increased in PD patients. The Kd values were unchanged. The difference in putaminal Bmax values between the opposite hemispheres correlated with the difference in the severity of parkinsonian motor symptoms between the two body sides (r = 0.69, p = 0.03). The present results show that there is both a relative and abs. increase in the no. of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease.302Payer, D. E.; Guttman, M.; Kish, S. J.; Tong, J.; Adams, J. R.; Rusjan, P.; Houle, S.; Furukawa, Y.; Wilson, A. A.; Boileau, I. D3 Dopamine receptor-preferring [11C]PHNO PET imaging in Parkinson patients with dyskinesia. Neurology 2016, 86, 224– 230, DOI: 10.1212/WNL.0000000000002285[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVGrt7Y%253D&md5=88822dc788366e98ec232ab0571a9c4eD3 dopamine receptor-preferring [11C]PHNO PET imaging in Parkinson patients with dyskinesiaPayer, Doris E.; Guttman, Mark; Kish, Stephen J.; Tong, Junchao; Adams, John R.; Rusjan, Pablo; Houle, Sylvain; Furukawa, Yoshiaki; Wilson, Alan A.; Boileau, IsabelleNeurology (2016), 86 (3), 224-230CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)To investigate whether levodopa-induced dyskinesias (LID) are assocd. with D3 overexpression in levodopa-treated humans with Parkinson disease (PD). In this case-control study, we used PET with the D3-preferring radioligand [11C]-(+)-PHNO to est. D2/3 receptor binding in patients with levodopa-treated PD with LID (n = 12) and without LID (n = 12), and healthy control subjects matched for age, sex, education, and mental status (n = 18). Compared to nondyskinetic patients, those with LID showed heightened [11C]-(+)-PHNO binding in the D3-rich globus pallidus. Both PD groups also showed higher binding than controls in the sensorimotor division of the striatum. In contrast, D2/3 binding in the ventral striatum was lower in patients with LID than without, possibly reflecting higher dopamine levels. Dopaminergic abnormalities contributing to LID may include elevated D2/3 binding in globus pallidus, perhaps reflecting D3 receptor upregulation. The findings support therapeutic strategies that target and diminish activity at D3 to prevent LID.303Seeman, P.; Wilson, A.; Gmeiner, P.; Kapur, S. Dopamine D2 and D3 receptors in human putamen, caudate nucleus, and globus pallidus. Synapse 2006, 60, 205– 211, DOI: 10.1002/syn.20298[Crossref], [PubMed], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvVGqsrg%253D&md5=1fb2b450e181d859c03256b8fa9f226cDopamine D2 and D3 receptors in human putamen, caudate nucleus, and globus pallidusSeeman, Philip; Wilson, Alan; Gmeiner, Peter; Kapur, ShitijSynapse (Hoboken, NJ, United States) (2006), 60 (3), 205-211CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)Because radioactive raclopride and radioactive (+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) are used to image dopamine (DA) D2 and D3 receptors in the striatum and globus pallidus in humans, the present study examd. the proportions of D2 and D3 receptors in postmortem tissues from these regions. Conflicting results were obtained when using a single concn. of remoxipride to occlude D2 receptors or using a single concn. of U99194A or FAUC 365 to occlude D3 receptors. However, using a range of concns. of FAUC 365, a D3-selective antagonist, to inhibit the binding [3H]raclopride or [3H]-(+)-PHNO to D3 receptors at low concns. (1-10 nM) and to inhibit ligand binding to D2 receptors at higher concns. (100-2000 nM), it was possible to measure the proportion of D2 and D3 receptors in the tissues. This method revealed that these 2 radioligands detected only D2 receptors in the dorsal putamen and the dorsal caudate nucleus, but detected a mixed population of 67% D2 and 33% D3 DA receptors in the ventral putamen, ventral caudate, and globus pallidus. The present findings are in good agreement with the known gene expression data for D2 and D3 receptors in these human brain regions.304Tziortzi, A. C.; Searle, G. E.; Tzimopoulou, S.; Salinas, C.; Beaver, J. D.; Jenkinson, M.; Laruelle, M.; Rabiner, E. A.; Gunn, R. N. Imaging dopamine receptors in humans with [11C]-(+)-PHNO: Dissection of D3 signal and anatomy. NeuroImage 2011, 54, 264– 277, DOI: 10.1016/j.neuroimage.2010.06.044[Crossref], [PubMed], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlCjsrnE&md5=59808003a4dad72b2f4f1c04b411c681Imaging dopamine receptors in humans with [11C]-(+)-PHNO: Dissection of D3 signal and anatomyTziortzi, Andri C.; Searle, Graham E.; Tzimopoulou, Sofia; Salinas, Cristian; Beaver, John D.; Jenkinson, Mark; Laruelle, Marc; Rabiner, Eugenii A.; Gunn, Roger N.NeuroImage (2011), 54 (1), 264-277CODEN: NEIMEF; ISSN:1053-8119. (Elsevier B.V.)[11C]-(+)-PHNO is a D3 preferring PET radioligand which has recently opened the possibility of imaging D3 receptors in the human brain in vivo. This imaging tool allows characterization of the distribution of D3 receptors in vivo and further investigation of their functional role. The specific [11C]-(+)-PHNO signal is a mixt. of D3 and D2 components with the relative magnitude of each component detd. by the regional receptor densities. An accurate and reproducible delineation of regions of interest (ROI) is therefore important for optimal anal. of human PET data. We present a set of anatomical guidelines for the delineation of D3 relevant ROIs including substantia nigra, hypothalamus, ventral pallidum/substantia innominata, ventral striatum, globus pallidus and thalamus. Delineation of these structures using this approach allowed for high intra- and inter-operator reproducibility. Subsequently we used a selective D3 antagonist to dissect the total [11C]-(+)-PHNO signal in each region into its D3 and D2 components and estd. the regional fraction of the D3 signal (f PHNO D3). In descending order of magnitude the following results for the f PHNO D3 were obtained: hypothalamus = 100%, substantia nigra = 100%, ventral pallidum/substantia innominata = 75%, globus pallidus = 65%, thalamus = 43%, ventral striatum = 26% and precommissural-ventral putamen = 6%. An automated approach for the delineation of these anatomical regions of interest was also developed and investigated in terms of its reproducibility and accuracy.305Payer, D. E.; Guttman, M.; Kish, S. J.; Tong, J.; Strafella, A.; Zack, M.; Adams, J. R.; Rusjan, P.; Houle, S.; Furukawa, Y.; Wilson, A. A.; Boileau, I. [11C]-(+)-PHNO PET imaging of dopamine D 2/3 receptors in Parkinson’s disease with impulse control disorders: [11C]PHNO binding in Parkinson’s disease. Mov. Disord. 2015, 30, 160– 166, DOI: 10.1002/mds.26135[Crossref], [PubMed], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit12rsLY%253D&md5=72a4e1ce35341c4ce8c0b35a12fec7d4[11C]-(+)-PHNO PET imaging of dopamine D2/3 receptors in Parkinson's disease with impulse control disordersPayer, Doris E.; Guttman, Mark; Kish, Stephen J.; Tong, Junchao; Strafella, Antonio; Zack, Martin; Adams, John R.; Rusjan, Pablo; Houle, Sylvain; Furukawa, Yoshiaki; Wilson, Alan A.; Boileau, IsabelleMovement Disorders (2015), 30 (2), 160-166CODEN: MOVDEA; ISSN:0885-3185. (Wiley-Blackwell)Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been assocd. with pathol. behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are assocd. with greater D3 dopamine receptor availability. We used positron emission tomog. (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [11C]-(+)-PHNO binding in D3-rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [11C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [11C]-(+)-PHNO binding is assocd. with D2 receptor levels, [11C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved. © 2015 International Parkinson and Movement Disorder Society.306Martinez, D.; Greene, K.; Broft, A.; Kumar, D.; Liu, F.; Narendran, R.; Slifstein, M.; Van Heertum, R.; Kleber, H. D. Lower level of endogenous dopamine in patients with cocaine dependence: Findings from PET imaging of D2/D3 receptors following acute dopamine depletion. Am. J. Psychiatry 2009, 166, 1170– 1177, DOI: 10.1176/appi.ajp.2009.08121801[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnmtFGisw%253D%253D&md5=6729c7b4fb2bfa296919785a6ed633e9Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletionMartinez Diana; Greene Kaitlin; Broft Allegra; Kumar Dileep; Liu Fei; Narendran Rajesh; Slifstein Mark; Van Heertum Ronald; Kleber Herbert DThe American journal of psychiatry (2009), 166 (10), 1170-7 ISSN:.OBJECTIVE: Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D(2)/D(3)) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D(2)/D(3) receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects. METHOD: Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [(11)C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole. RESULTS: Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [(11)C]raclopride binding following AMPT administration. The increase in [(11)C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum. CONCLUSIONS: The decrease in striatal D(2)/D(3 )receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.307Martinez, D.; Narendran, R. Imaging Neurotransmitter Release by Drugs of Abuse. In Behavioral Neuroscience of Drug Addiction; Self, D. W., Staley Gottschalk, J. K., Eds.; Current Topics in Behavioral Neurosciences; Springer: Berlin, Heidelberg, 2010; Vol. 3, pp 219– 245.308Fowler, J.; MacGregor, R.; Wolf, A.; Arnett, C.; Dewey, S.; Schlyer, D.; Christman, D.; Logan, J.; Smith, M.; Sachs, H. Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science 1987, 235, 481– 485, DOI: 10.1126/science.3099392[Crossref], [PubMed], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXhtlCis7s%253D&md5=ade47b744d08e5ce8f34664d96455a8eMapping human brain monoamine oxidase A and B with carbon-11-labeled suicide inactivators and PETFowler, J. S.; MacGregor, R. R.; Wolf, A. P.; Arnett, C. D.; Dewey, S. L.; Schlyer, D.; Christman, D.; Logan, J.; Smith, M.; et al.Science (Washington, DC, United States) (1987), 235 (4787), 481-5CODEN: SCIEAS; ISSN:0036-8075.The regional distribution of MAO types A and B were identified in human brain in vivo with i.v. injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and position emission tomog. (PET). The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in 1 subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.309Vuorimaa, A.; Rissanen, E.; Airas, L. In vivo PET imaging of adenosine 2A receptors in neuroinflammatory and neurodegenerative disease. Contrast Media Mol. Imaging 2017, 2017, 6975841, DOI: 10.1155/2017/6975841[Crossref], [PubMed], [CAS], Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvitF2ksg%253D%253D&md5=3c37afa18a3c2b0ef7b0aaaf36786200In Vivo PET Imaging of Adenosine 2A Receptors in Neuroinflammatory and Neurodegenerative DiseaseVuorimaa Anna; Rissanen Eero; Airas Laura; Vuorimaa Anna; Rissanen Eero; Airas LauraContrast media & molecular imaging (2017), 2017 (), 6975841 ISSN:.Adenosine receptors are G-protein coupled P1 purinergic receptors that are broadly expressed in the peripheral immune system, vasculature, and the central nervous system (CNS). Within the immune system, adenosine 2A (A2A) receptor-mediated signaling exerts a suppressive effect on ongoing inflammation. In healthy CNS, A2A receptors are expressed mainly within the neurons of the basal ganglia. Alterations in A2A receptor function and expression have been noted in movement disorders, and in Parkinson's disease pharmacological A2A receptor antagonism leads to diminished motor symptoms. Although A2A receptors are expressed only at a low level in the healthy CNS outside striatum, pathological challenge or inflammation has been shown to lead to upregulation of A2A receptors in extrastriatal CNS tissue, and this has been successfully quantitated using in vivo positron emission tomography (PET) imaging and A2A receptor-binding radioligands. Several radioligands for PET imaging of A2A receptors have been developed in recent years, and A2A receptor-targeting PET imaging may thus provide a potential additional tool to evaluate various aspects of neuroinflammation in vivo. This review article provides a brief overview of A2A receptors in healthy brain and in a selection of most important neurological diseases and describes the recent advances in A2A receptor-targeting PET imaging studies.310Cybulska, K.; Perk, L.; Booij, J.; Laverman, P.; Rijpkema, M. Huntington’s disease: A review of the known PET imaging biomarkers and targeting radiotracers. Molecules 2020, 25, 482, DOI: 10.3390/molecules25030482[Crossref], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXktVOjsrY%253D&md5=89ec0a3ecbf952f3e9e035e50e8e4180Huntington's disease: a review of the known PET imaging biomarkers and targeting radiotracersCybulska, Klaudia; Perk, Lars; Booij, Jan; Laverman, Peter; Rijpkema, MarkMolecules (2020), 25 (3), 482CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomog. (PET) studies relating to HD was performed, including clin. and preclin. data. PET is a powerful tool for visualisation of the HD pathol. by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed mol. snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognize particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochem. picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.311Ishiwata, K.; Ogi, N.; Hayakawa, N.; Oda, K.; Nagaoka, T.; Toyama, H.; Suzuki, F.; Endo, K.; Tanaka, A.; Senda, M. Adenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: Comparison with the dopamine receptor imaging. Ann. Nucl. Med. 2002, 16, 467– 475, DOI: 10.1007/BF02988643[Crossref], [PubMed], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnvFKisA%253D%253D&md5=95b207f690f7a3cefb32f8bdf8dd98cbAdenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: comparison with the dopamine receptor imagingIshiwata, Kiichi; Ogi, Nobuo; Hayakawa, Nobutaka; Oda, Keiichi; Nagaoka, Tsukasa; Toyama, Hinako; Suzuki, Fumio; Endo, Kazutoyo; Tanaka, Akira; Senda, MichioAnnals of Nuclear Medicine (2002), 16 (7), 467-475CODEN: ANMEEX; ISSN:0914-7187. (Japanese Society of Nuclear Medicine)We proposed [11C]KF18446 as a selective radioligand for mapping the adenosine A2A receptors being highly enriched in the striatum by positron emission tomog. (PET). In the present study, we investigated whether [11C]KF18446 PET can detect the change in the striatal adenosine A2A receptors in the rat after unilateral injection of an excitotoxin quinolinic acid into the striatum, a Huntington's disease model, to demonstrate the usefulness of [11C]KF18446. The extent of the striatal lesion was identified based on MRI, to which the PET was co-registered. The binding potential of [11C]KF18446 significantly decreased in the quinolinic acid-lesioned striatum. The decrease was comparable to the decrease in the potential of [11C]raclopride binding to dopamine D2 receptors in the lesioned striatum, but seemed to be larger than the decrease in the potential of [11C]SCH 23390 binding to dopamine D1 receptors. Ex vivo and in vitro autoradiog. validated the PET signals. We concluded that [11C]KF18446 PET can detect change in the adenosine A2A receptors in the rat model, and will provide a new diagnostic tool for characterizing post-synaptic striatopallidal neurons in the striatum.312Ishiwata, K.; Noguchi, J.; Wakabayashi, S.; Shimada, J.; Ogi, N.; Nariai, T.; Tanaka, A.; Endo, K.; Suzuki, F.; Senda, M. 11C-labeled KF18446: A potential central nervous system adenosine A2a receptor ligand. J. Nucl. Med. 2000, 41, 345– 354[PubMed], [CAS], Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhtlGnt7w%253D&md5=3a0baaa69c597e511b4901d99d17da1211C-labeled KF18446: a potential central nervous system adenosine A2a receptor ligandIshiwata, Kiichi; Noguchi, Junko; Wakabayashi, Shin-Ichi; Shimada, Junichi; Ogi, Nobuo; Nariai, Tadashi; Tanaka, Akira; Endo, Kazutoyo; Suzuki, Fumio; Senda, MichioJournal of Nuclear Medicine (2000), 41 (2), 345-354CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine, Inc.)To develop PET ligands for mapping central nervous system (CNS) adenosine A2a receptors that are localized in the striatum and are coupled with dopamine receptors, 3 11C-labeled xanthine-type adenosine A2a antagonists, [11C]KF18446 ([7-methyl-11C]-(E) -8-(3,4,5-trimethoxystyryl)-1,3,7- trimethylxanthine), [11C]KF19631 ([7-methyl-11C]- (E)-1,3-diallyl-7-methyl-8- (3,4,5- trimethoxystyryl-)xanthine), and [11C]CSC ([7-methyl-11C] -8-chlorostyrylcaffeine), were compared with [11C]KF17837 ([7-methyl-11C]- (E)-8-(3,4-dimethoxystyryl) -1,3-dipropyl-7- methylxanthine). The regional brain uptake of the tracers, the effect of the coinjected adenosine antagonists on the uptake, and the metab. were studied in mice. In rats, the regional brain uptake of the tracers was visualized by ex vivo autoradiog. (ARG). The A2a receptor binding of antagonist 1 was also measured by in vitro ARG. Imaging of the monkey brain was performed with PET with antagonist 1. In mice, the highest striatal uptake was found for antagonist 1 followed by antagonists 2 and 4. The uptake was inhibited by each of 3 KF compds. and by CSC, but not by an A1 antagonist KF15372. Another selective nonxanthine-type A2a antagonist SCH 58261 significantly decreased the striatal uptake of only antagonist 1, the labeled metabolites of which were less than 20% in the plasma 30 min postinjection, but were negligible in the brain tissue. In ex vivo ARG, antagonist 1 showed the highest striatal uptake and the highest uptake ratio of the striatum to the other brain regions. A high and selective binding of antagonist 1 to the striatum was also confirmed by in vitro ARG. PET with antagonist 1 visualized adenosine A2a receptors in the monkey striatum. These results indicate that antagonist 1 ([11C]KF18446) is the most suitable PET ligand for mapping adenosine A2a receptors in the CNS.313Paul, S.; Khanapur, S.; Sijbesma, J. W.; Ishiwata, K.; Elsinga, P. H.; Meerlo, P.; Dierckx, R. A.; van Waarde, A. Use of 11C-MPDX and PET to study adenosine A1 receptor occupancy by nonradioactive agonists and antagonists. J. Nucl. Med. 2014, 55, 315– 320, DOI: 10.2967/jnumed.113.130294[Crossref], [PubMed], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltlaqtLk%253D&md5=097d76539235c631097340fc4a9915faUse of 11C-MPDX and PET to study adenosine A1 receptor occupancy by nonradioactive agonists and antagonistsPaul, Soumen; Khanapur, Shivashankar; Sijbesma, Jurgen W.; Ishiwata, Kiichi; Elsinga, Philip H.; Meerlo, Peter; Dierckx, Rudi A.; van Waarde, ArenJournal of Nuclear Medicine (2014), 55 (2), 315-320CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)Adenosine A1 receptors (A1Rs) in human and rodent brains can be visualized with the radioligand 8-dicyclopropylmethyl-1-11C-methyl-3-propylxanthine (11C-MPDX) and PET. Here we investigated whether A1R occupancy by nonradioactive agonists and antagonists can be assessed with this technique. Methods: Small-animal PET scans with arterial blood sampling were obtained for 4 groups of isoflurane-anesthetized Wistar rats: controls (n = 7); pretreated with a centrally active A1R agonist, N6-cyclopentyladenosine (CPA; 0.25 mg/kg i.p.; dissocn. const., 0.48 nM; n = 7); pretreated with a moderate dose of caffeine (antagonist for A1Rs and adenosine A2A receptors; 4 mg/kg i.p.; dissocn. const., 11 μM; n = 6); and pretreated with a high dose of caffeine (40 mg/kg i.p.; n = 6). Results: The administration of CPA resulted in a strong redn. (>50%) in the heart rate, and caffeine administration resulted in a small increase (10%-15%). A caffeine dose of 4 mg/kg (n = 6) resulted in 65.9% A1R occupancy, and a dose of 40 mg/kg (n = 6) resulted in 98.5% occupancy (calcd. from a modified Lassen plot). However, the administration of CPA resulted in an increase in 11C-MPDX binding in the brain. Conclusion: Small-animal PET with 11C-MPDX can be used to assess antagonist but not agonist binding at A1Rs. Changes in tracer uptake after the administration of CPA resembled previously reported changes induced by treatment of rats with ethanol and an adenosine kinase inhibitor (ABT702). Thus, the administration of an exogenous agonist or increasing the level of an endogenous agonist have similar effects. Agonists and antagonists may bind to different sites on the A1R protein having allosteric interactions.314Hayashi, S.; Inaji, M.; Nariai, T.; Oda, K.; Sakata, M.; Toyohara, J.; Ishii, K.; Ishiwata, K.; Maehara, T. Increased binding potential of brain adenosine A 1 receptor in chronic stages of patients with diffuse axonal injury measured with [1-methyl- 11C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine positron emission tomography imaging. Journal of Neurotrauma. 2018, 35, 25– 31, DOI: 10.1089/neu.2017.5006[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cjps1Wrtw%253D%253D&md5=eae75f47be1869083490310c4b7ab8caIncreased Binding Potential of Brain Adenosine A1 Receptor in Chronic Stages of Patients with Diffuse Axonal Injury Measured with [1-methyl-(11)C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine Positron Emission Tomography ImagingHayashi Shihori; Inaji Motoki; Nariai Tadashi; Maehara Taketoshi; Oda Keiichi; Sakata Muneyuki; Toyohara Jun; Ishii Kenji; Ishiwata Kiichi; Ishiwata Kiichi; Ishiwata KiichiJournal of neurotrauma (2018), 35 (1), 25-31 ISSN:.The positron emission tomography (PET) radioligand for adenosine A1 receptor (A1R) [1-methyl-(11)C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX) has recently been developed for human brain imaging. In the present study, we evaluated the alteration of the A1R in patients with diffuse axonal injury (DAI) in chronic stage in vivo. Ten patients with DAI (7 men and 3 women) were included in this study. Three PET examinations were sequentially performed to measure A1R binding with (11)C-MPDX, glucose metabolism with (18)F-fluorodeoxyglucose (FDG), and central benzodiazepine receptor binding with (11)C-flumazenil (FMZ), and decreases of (11)C-FMZ uptake indicate neuronal loss. (11)C- MPDX did not depict any lesion with significantly decreased nondisplaceable binding potential (BPND) in comparison to healthy controls (14 men) in region of interest (ROI) analysis. Instead, it showed a significant increase of BPND in the lower frontal and posterior cingulate cortexes and rolandic area (p < 0.05) in ROI analysis. In (18)F-FDG PET, the standardized uptake values (SUVs) ratio to the whole brain were decreased in anterior and posterior cingulate gyrus compared to controls (14 men and 9 women; p < 0.01). In (11)C-FMZ PET, the SUV ratio to the cerebellum was decreased in anterior cingulate gyrus in ROI analysis (controls, 9 men and 6 women; p < 0.01). The area with significantly increased (11)C-MPDX binding, lower frontal cortex, rolandic area, and posterior cingulate gyrus, did not overlap with the areas of neuronal loss detected by decreased (11)C-FMZ binding and did not completely overlap with area of reduced(18)F-FDG uptake. We obtained the first (11)C-MPDX PET images reflecting the A1R BPND in human DAI brain in vivo. (11)C-MPDX depicted increased A1R BPND in the areas surrounding the injured brain, whereas (18)F-FDG demonstrated reduction throughout the brain. The results suggested that A1R might continuously confer neuroprotective or neuromodulatory effects in DAI even in the chronic stage.315Mishina, M.; Ishii, K.; Kimura, Y.; Suzuki, M.; Kitamura, S.; Ishibashi, K.; Sakata, M.; Oda, K.; Kobayashi, S.; Kimura, K.; Ishiwata, K. Adenosine A 1 receptors measured with 11 C-MPDX PET in early Parkinson’s disease. Synapse 2017, 71, e21979 DOI: 10.1002/syn.21979316Lahesmaa, M.; Oikonen, V.; Helin, S.; Luoto, P.; U Din, M.; Pfeifer, A.; Nuutila, P.; Virtanen, K. A. Regulation of human brown adipose tissue by adenosine and A2A receptors – studies with [15O]H2O and [11C]TMSX PET/CT. Eur. J. Nucl. Med. Mol. Imaging 2019, 46, 743– 750, DOI: 10.1007/s00259-018-4120-2[Crossref], [PubMed], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFSqtLjP&md5=bd7eb3664279f1ebd18ed7afc669f64aRegulation of human brown adipose tissue by adenosine and A2A receptors - studies with [15O]H2O and [11C]TMSX PET/CTLahesmaa, Minna; Oikonen, Vesa; Helin, Semi; Luoto, Pauliina; U Din, Mueez; Pfeifer, Alexander; Nuutila, Pirjo; Virtanen, Kirsi A.European Journal of Nuclear Medicine and Molecular Imaging (2019), 46 (3), 743-750CODEN: EJNMA6; ISSN:1619-7070. (Springer)Brown adipose tissue (BAT) has emerged as a potential target to combat obesity and diabetes, but novel strategies to activate BAT are needed. Adenosine and A2A receptor (A2AR) agonism activate BAT in rodents, and endogenous adenosine is released locally in BAT as a byproduct of noradrenaline, but physiol. data from humans is lacking. The purpose of this pilot study was to investigate the effects of exogenous adenosine on human BAT perfusion, and to det. the d. of A2ARs in human BAT in vivo for the first time, using PET/CT imaging. Healthy, lean men (n = 10) participated in PET/CT imaging with two radioligands. Perfusion of BAT, white adipose tissue (WAT) and muscle was quantified with [15O]H2O at baseline, during cold exposure and during i.v. administration of adenosine. A2AR d. of the tissues was quantified with [11C]TMSX at baseline and during cold exposure. Adenosine increased the perfusion of BAT even more than cold exposure (baseline 8.3 ± 4.5, cold 19.6 ± 9.3, adenosine 28.6 ± 7.9 μmol/100 g/min, p < 0.01). Distribution vol. of [11C]TMSX in BAT was significantly lower during cold exposure compared to baseline. In cold, low [11C]TMSX binding coincided with high concns. of noradrenaline. Adenosine administration caused a maximal perfusion effect in human supraclavicular BAT, indicating increased oxidative metab. Cold exposure increased noradrenaline concns. and decreased the d. of A2AR available for radioligand binding in BAT, suggesting augmented release of endogenous adenosine. Our results show that adenosine and A2AR are relevant for activation of human BAT, and A2AR provides a future target for enhancing BAT metab.317Zhou, X.; Khanapur, S.; Huizing, A. P.; Zijlma, R.; Schepers, M.; Dierckx, R. A. J. O.; van Waarde, A.; de Vries, E. F. J.; Elsinga, P. H. Synthesis and preclinical evaluation of 2-(2-furanyl)-7-[2-[4-[4-(2-[11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e ][1,2,4]triazolo[1,5- c ]pyrimidine-5-amine ([11C]preladenant) as a PET tracer for the imaging of cerebral adenosine A 2A receptors. J. Med. Chem. 2014, 57, 9204– 9210, DOI: 10.1021/jm501065t[ACS Full Text], [CAS], Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1OktLfM&md5=eef1c94bbc68e8bc456de136d5bd334eSynthesis and Preclinical Evaluation of 2-(2-Furanyl)-7-[2-[4-[4-(2-[11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine ([11C]Preladenant) as a PET Tracer for the Imaging of Cerebral Adenosine A2A ReceptorsZhou, Xiaoyun; Khanapur, Shivashankar; Huizing, Anja P.; Zijlma, Rolf; Schepers, Marianne; Dierckx, Rudi A. J. O.; van Waarde, Aren; de Vries, Erik F. J.; Elsinga, Philip H.Journal of Medicinal Chemistry (2014), 57 (21), 9204-9210CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)2-(2-Furanyl)-7-[2-[4-[4-(2-[11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine [11C]-3 ([11C]Preladenant) was developed for mapping cerebral adenosine A2A receptors (A2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD), and in vitro autoradiog. (ARG) expts. Regional brain uptake of [11C]-3 was consistent with known A2ARs distribution, with highest uptake in striatum. The results indicate that [11C]-3 has favorable brain kinetics and exhibits suitable characteristics as an A2AR PET tracer.318Zhou, X.; Elsinga, P. H.; Khanapur, S.; Dierckx, R. A. J. O.; de Vries, E. F. J.; de Jong, J. R. Radiation dosimetry of a novel adenosine A2A receptor radioligand [11C]preladenant based on PET/CT imaging and ex vivo biodistribution in rats. Mol. Imaging Biol. 2017, 19, 289– 297, DOI: 10.1007/s11307-016-0992-3[Crossref], [PubMed], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVSlsr3O&md5=667c9b52dbfd01da31b92b34147b22dfRadiation Dosimetry of a Novel Adenosine A2A Receptor Radioligand [11C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in RatsZhou, Xiaoyun; Elsinga, Philip H.; Khanapur, Shivashankar; Dierckx, Rudi A. J. O.; de Vries, Erik F. J.; de Jong, Johan R.Molecular Imaging and Biology (2017), 19 (2), 289-297CODEN: MIBOCZ; ISSN:1860-2002. (Springer)Purpose: [11C]Preladenant was developed as a novel adenosine A2A receptor PET radioligand. The aim of this study was to det. the radiation dosimetry of [11C]preladenant and to investigate whether dosimetry estn. based on organ harvesting can be replaced by positron emission tomog. (PET)/x-ray computed tomog. (CT) imaging in rats. Procedures: Male Wistar rats (n = 35) were i.v. injected with [11C]preladenant. The tracer biodistribution was detd. by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty vols. of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical ref. The dynamic time-activity curves were used to calc. organ residence times (RTs). Human radiation dosimetry ests., derived from rat data, were calcd. with OLINDA/EXM 1.1. Results: PET-imaging and organ-harvesting estd. comparable organ RTs, with differences of 6-27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, resp. The crit. organ was the small intestine with a dose of 25 μSv/MBq. The EDs (EDs) calcd. from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 μSv/MBq, resp., using the International Commission on Radiol. Protection 60 tissue weighting factors. Conclusions: The ED of [11C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estn. of the radiation dosimetry of [11C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the no. of lab. animals required.319Elmenhorst, D.; Kroll, T.; Wedekind, F.; Weisshaupt, A.; Beer, S.; Bauer, A. In vivo kinetic and steady-state quantification of 18F-CPFPX binding to rat cerebral A1 adenosine receptors: Validation by displacement and autoradiographic experiments. J. Nucl. Med. 2013, 54, 1411– 1419, DOI: 10.2967/jnumed.112.115576[Crossref], [PubMed], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVejsr7J&md5=e411324166cbb6e6ed5c655dd2ca5d8aIn vivo kinetic and steady-state quantification of 18F-CPFPX binding to rat cerebral A1 adenosine receptors: validation by displacement and autoradiographic experimentsElmenhorst, David; Kroll, Tina; Wedekind, Franziska; Weisshaupt, Angela; Beer, Simone; Bauer, AndreasJournal of Nuclear Medicine (2013), 54 (8), 1411-1419CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)In vivo imaging of the A1 adenosine receptor (A1AR) using 18F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (18F-CPFPX) and PET has become an important tool for studying physiol. and pathol. states of the human brain. However, dedicated exptl. settings for small-animal studies are still lacking. The aim of the present study was therefore to develop and evaluate suitable pharmacokinetic models for the quantification of the cerebral A1AR in high-resoln. PET. Methods: On a dedicated animal PET scanner, 15 rats underwent 18F-CPFPX PET scans of 120-min duration. In all animals, arterial blood samples were drawn and cor. for metabolites. The radioligand was injected either as a bolus or as a bolus plus const. infusion. For the definition of unspecific binding, the A1AR selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was applied. After PET, the brains of 9 animals were dissected and in vitro satn. binding was performed using high-resoln. 3H-DPCPX autoradiog. Results: The kinetics of 18F-CPFPX were well described by either compartmental or noncompartmental models based on arterial input function. The resulting distribution vol. ratio correlated with a low bias toward identity with the binding potential derived from a ref. region (olfactory bulb) approach. Furthermore, PET quantification correlated significantly with autoradiog. in vitro data. Blockade of the A1AR with DPCPX identified specific binding of about 45% in the ref. region olfactory bulb. Conclusion: The present study provides evidence that 18F-CPFPX PET based on a ref. tissue approach can be performed quant. in rodents in selected applications. Specific binding in the ref. region needs careful consideration for quant. investigations.320Kreft, S.; Bier, D.; Holschbach, M. H.; Schulze, A.; Coenen, H. H. New potent A1 adenosine receptor radioligands for positron emission tomography. Nucl. Med. Biol. 2017, 44, 69– 77, DOI: 10.1016/j.nucmedbio.2016.09.004[Crossref], [PubMed], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVSntL%252FL&md5=4cfb2a1568f9a31da4578b92d1147739New potent A1 adenosine receptor radioligands for positron emission tomographyKreft, Sabrina; Bier, Dirk; Holschbach, Marcus H.; Schulze, Annette; Coenen, Heinz H.Nuclear Medicine and Biology (2017), 44 (), 69-77CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is meanwhile an accepted receptor ligand to examine the A1 adenosine receptor (A1AR) in humans by positron emission tomog. (PET). A major drawback of this compd. is its rather fast metabolic degrdn. in vivo. Therefore two new xanthine derivs., namely 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (CBCPM; 5) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (CPMMCB; 6) were designed and synthesized as potential alternatives to CPFPX. In membrane binding studies both compds. showed nanomolar affinity for the A1AR. In vitro autoradiog. studies of [18F]5 and [18F]6, using rat brain slices, showed the expected accumulation in regions known to have a high adenosine A1 receptor expression while exhibiting the necessary low unspecific binding. However, in vitro metabolite studies using human liver microsomes revealed a comparable metabolic degrdn. rate for both new xanthine derivs. and CPFPX.321Lindemann, M.; Hinz, S.; Deuther-Conrad, W.; Namasivayam, V.; Dukic-Stefanovic, S.; Teodoro, R.; Toussaint, M.; Kranz, M.; Juhl, C.; Steinbach, J.; Brust, P.; Müller, C. E.; Wenzel, B. Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptor. Bioorg. Med. Chem. 2018, 26, 4650– 4663, DOI: 10.1016/j.bmc.2018.07.045[Crossref], [PubMed], [CAS], Google Scholar321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsV2lurzP&md5=9cfeb12865ae0af6f1a1f87144d4e2c9Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptorLindemann, Marcel; Hinz, Sonja; Deuther-Conrad, Winnie; Namasivayam, Vigneshwaran; Dukic-Stefanovic, Sladjana; Teodoro, Rodrigo; Toussaint, Magali; Kranz, Mathias; Juhl, Cathleen; Steinbach, Joerg; Brust, Peter; Mueller, Christa E.; Wenzel, BarbaraBioorganic & Medicinal Chemistry (2018), 26 (16), 4650-4663CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)On the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a-c) were synthesized contg. a 2-fluoropyridine moiety suitable for 18F-labeling. Compd. 7a was docked into a homol. model of the A2B receptor based on X-ray structures of the related A2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were detd. at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A1 receptor, 7a was radiolabeled as the most suitable candidate (Ki(A2B) = 4.24 nM) in order to perform in vivo studies in mice with the aim to est. fundamental pharmacokinetic characteristics of the compd. class. Organ distribution studies and a single PET study demonstrated brain uptake of [18F]7a with a standardized uptake value (SUV) of ≈1 at 5 min post injection followed by a fast wash out. Metab. studies of [18F]7a in mice revealed the formation of a blood-brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivs. with improved binding properties and metabolic stability in vivo.322Niccolini, F.; Haider, S.; Reis Marques, T.; Muhlert, N.; Tziortzi, A. C.; Searle, G. E.; Natesan, S.; Piccini, P.; Kapur, S.; Rabiner, E. A.; Gunn, R. N.; Tabrizi, S. J.; Politis, M. Altered PDE10A expression detectable early before symptomatic onset in Huntington’s disease. Brain 2015, 138, 3016– 3029, DOI: 10.1093/brain/awv214[Crossref], [PubMed], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252Flt1KqtA%253D%253D&md5=35244382e3e08926abebd5ce93bb061bAltered PDE10A expression detectable early before symptomatic onset in Huntington's diseaseNiccolini Flavia; Politis Marios; Haider Salman; Tabrizi Sarah J; Reis Marques Tiago; Natesan Sridhar; Kapur Shitij; Muhlert Nils; Tziortzi Andri C; Searle Graham E; Piccini Paola; Rabiner Eugenii A; Gunn Roger NBrain : a journal of neurology (2015), 138 (Pt 10), 3016-29 ISSN:.There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.323Hebb, A. L. O.; Robertson, H. A.; Denovan-Wright, E. M. Striatal phosphodiesterase MRNA and protein levels are reduced in Huntington’s disease transgenic mice prior to the onset of motor symptoms. Neuroscience 2004, 123, 967– 981, DOI: 10.1016/j.neuroscience.2003.11.009[Crossref], [PubMed], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvFKgsg%253D%253D&md5=f274758b2f39ce57fae14cb76d61ff50Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington's disease transgenic mice prior to the onset of motor symptomsHebb, A. L. O.; Robertson, H. A.; Denovan-Wright, E. M.Neuroscience (Oxford, United Kingdom) (2004), 123 (4), 967-981CODEN: NRSCDN; ISSN:0306-4522. (Elsevier Science Ltd.)Inheritance of a single copy of the gene encoding huntingtin (HD) with an expanded polyglutamine-encoding CAG repeat leads to neuronal dysfunction, neurodegeneration and the development of the symptoms of Huntington's disease (HD). The authors have found that the steady-state mRNA levels of two members of the phosphodiesterase (PDE) multi-gene family decrease over time in the striatum of R6 transgenic HD mice relative to age-matched wild-type littermates. Phosphodiesterase 10A (PDE10A) mRNA and protein levels decline in the striatum of R6/1 and R6/2 HD mice prior to motor symptom development. The rate of redn. in PDE10A protein correlates with the rate of decline of the message and the decrease in PDE10A mRNA and protein is more rapid in R6/2 compared with R6/1 mice. Both PDE10A protein and mRNA, therefore, decline to min. levels prior to the onset of overt phys. symptoms in both strains of transgenic mice. Moreover, protein levels of PDE10A are decreased in the caudate-putamen of grade 3 HD patients compared with age-matched neuropathol. normal controls. Striatal PDE1B mRNA levels also decline in R6/1 and R6/2 HD mice; however, the decrease in striatal PDE10A levels (>60%) was greater than that obsd. for PDE1B and immediately preceded the onset of motor symptoms. In contrast, PDE4A mRNA levels are relatively low in the striatum and do not differ between age-matched wild-type and transgenic HD mice. This suggests that the regulation of PDE10A and PDE1B, but not PDE4A, mRNA levels is dependent on the relative expression of or no. of CAG repeats within the human HD transgene. The loss of phosphodiesterase activity may lead to dysregulation of cAMP and cGMP levels in the striatum, a region of the brain that contributes to the control of movement and cognition.324Tu, Z.; Xu, J.; Jones, L. A.; Li, S.; Mach, R. H. Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: Radiosynthesis, in vitro and in vivo evaluation. Nucl. Med. Biol. 2010, 37, 509– 516, DOI: 10.1016/j.nucmedbio.2009.12.012[Crossref], [PubMed], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlvVeju7o%253D&md5=4909a2ea1c548910efc84a2369b38416Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluationTu, Zhude; Xu, Jinbin; Jones, Lynne A.; Li, Shihong; Mach, Robert H.Nuclear Medicine and Biology (2010), 37 (4), 509-516CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase (PDE) 10A with IC50 values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiol. role of PDE10A. Here, we report the radiosynthesis of [11C]papaverine and the in vitro and in vivo evaluation of [11C]papaverine as a potential positron emission tomog. (PET) radiotracer for imaging PDE10A in the central nervous system (CNS). The radiosynthesis of papaverine with 11C was achieved by O-methylation of the corresponding des-Me precursor with [11C]methyl iodide. [11C]papaverine was obtained with ∼70% radiochem. yield and a specific activity >10 Ci/μmol. In vitro autoradiog. studies of rat and monkey brain sections revealed selective binding of [11C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [11C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. MicroPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [11C]papaverine from brain. Our initial evaluation suggests that despite papaverine's utility for in vitro studies and as a pharmaceutical tool, [11C]papaverine is not an ideal radioligand for clin. imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.325Liu, H.; Jin, H.; Yue, X.; Zhang, X.; Yang, H.; Li, J.; Flores, H.; Su, Y.; Perlmutter, J. S.; Tu, Z. Preclinical evaluation of a promising C-11 labeled PET tracer for imaging phosphodiesterase 10A in the brain of living subject. NeuroImage 2015, 121, 253– 262, DOI: 10.1016/j.neuroimage.2015.07.049[Crossref], [PubMed], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yhtbvJ&md5=09bcfb0fa42e4deaadc22344fdbf8061Preclinical evaluation of a promising C-11 labeled PET tracer for imaging phosphodiesterase 10A in the brain of living subjectLiu, Hui; Jin, Hongjun; Yue, Xuyi; Zhang, Xiang; Yang, Hao; Li, Junfeng; Flores, Hubert; Su, Yi; Perlmutter, Joel S.; Tu, ZhudeNeuroImage (2015), 121 (), 253-262CODEN: NEIMEF; ISSN:1053-8119. (Elsevier Inc.)Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling. A PET tracer for PDE10A may serve as a tool to evaluate PDE10A expression in vivo in central nervous system disorders with striatal pathol. Here, we further characterized the binding properties of a previously reported radioligand we developed for PDE10A, [11C]TZ1964B, in rodents and nonhuman primates (NHPs). The tritiated counterpart [3H]TZ1964B was used for in vitro binding characterizations in rat striatum homogenates and in vitro autoradiog. studies in rat brain slices. The carbon-11 labeled [11C]TZ1964B was utilized in the ex vivo autoradiog. studies for the brain of rats and microPET imaging studies for the brain of NHPs. MicroPET scans of [11C]TZ1964B in NHPs were conducted at baseline, as well as with using a selective PDE10A inhibitor MP-10 for either pretreatment or displacement. The in vivo regional target occupancy (Occ) was obtained by pretreating with different doses of MP-10 (0.05-2.00 mg/kg). Both in vitro binding assays and in vitro autoradiog. studies revealed a nanomolar binding affinity of [3H]TZ1964B to the rat striatum. The striatal binding of [3H]TZ1964B and [11C]TZ1964B was either displaced or blocked by MP-10 in rats and NHPs. Autoradiog. and microPET imaging confirmed that the specific binding of the radioligand was found in the striatum but not in the cerebellum. Blocking studies also confirmed the suitability of the cerebellum as an appropriate ref. region. The binding potentials (BPND) of [11C]TZ1964B in the NHP striatum that were calcd. using either the Logan ref. model (LoganREF, 3.96 ± 0.17) or the simplified ref. tissue model (SRTM, 4.64 ± 0.47), with the cerebellum as the ref. region, was high and had good reproducibility. The occupancy studies indicated a MP-10 dose of 0.31 ± 0.09 mg/kg (LoganREF)/0.45 ± 0.17 mg/kg (SRTM) occupies 50% striatal PDE10A binding sites. Studies in rats and NHPs demonstrated radiolabeled TZ1964B has a high binding affinity and good specificity for PDE10A, as well as favorable in vivo pharmacokinetic properties and binding profiles. Our data suggests that [11C]TZ1964B is a promising radioligand for in vivo imaging PDE10A in the brain of living subject.326Liu, H.; Jin, H.; Luo, Z.; Yue, X.; Zhang, X.; Flores, H.; Su, Y.; Perlmutter, J. S.; Tu, Z. In vivo characterization of two 18F-labeled PDE10A PET radioligands in nonhuman primate brains. ACS Chem. Neurosci. 2018, 9, 1066– 1073, DOI: 10.1021/acschemneuro.7b00458[ACS Full Text], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFOntb8%253D&md5=62dd91b34d4386004051c2809afa3899In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate BrainsLiu, Hui; Jin, Hongjun; Luo, Zonghua; Yue, Xuyi; Zhang, Xiang; Flores, Hubert; Su, Yi; Perlmutter, Joel S.; Tu, ZhudeACS Chemical Neuroscience (2018), 9 (5), 1066-1073CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Positron emission tomog. (PET) with phosphodiesterase 10A (PDE10A) specific radioligands provides a noninvasive and quant. imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. We recently reported two potent 18F-labeled PDE10A radioligands (18F-TZ19106B and 18F-TZ8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. Herein, we focused on in vivo characterization of 18F-TZ19106B and 18F-TZ8110 to identify a suitable radioligand for imaging PDE10A in vivo. We directly compared microPET studies of these two radiotracers in adult male Macaca fascicularis nonhuman primates (NHPs). 18F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than 18F-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BPND) estd. using ref.-based modeling anal. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of 18F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of 18F-TZ19106B binding to varying no. of specific binding sites using escalating doses of MP-10 blockade (0.3, 0.5, 1.0, 1.5, and 2.0 mg/kg). Pretreatment with a dopamine D2-like receptor antagonist enhanced the striatal uptake of 18F-TZ19106B. Our results indicate that 18F-TZ19106B is a promising radioligand candidate for imaging PDE10A in vivo and it may be used to det. target engagement of PDE10A inhibitors and serve as a tool to evaluate the effect of novel antipsychotic therapies.327Li, J.; Zhang, X.; Jin, H.; Fan, J.; Flores, H.; Perlmutter, J. S.; Tu, Z. Synthesis of fluorine-containing phosphodiesterase 10A (PDE10A) inhibitors and the in vivo evaluation of F-18 labeled PDE10A PET tracers in rodent and nonhuman primate. J. Med. Chem. 2015, 58, 8584– 8600, DOI: 10.1021/acs.jmedchem.5b01205[ACS Full Text], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1SlsLbO&md5=4fe61e4415a08cc9ffc7cb0c0734b541Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman PrimateLi, Junfeng; Zhang, Xiang; Jin, Hongjun; Fan, Jinda; Flores, Hubert; Perlmutter, Joel S.; Tu, ZhudeJournal of Medicinal Chemistry (2015), 58 (21), 8584-8600CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of fluorine-contg. PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10 (I). Twenty of the 22 new analogs had high potency and selectivity for PDE10A (<5 nM). Seven F-18 labeled compds. were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ∼2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a-d [II: R1 = 4-fluoroquinol-2-yl, 4-(fluoromethyl)quinolin-2-yl, 4-(3-fluoropropyl)quinolin-2-yl, and 4-(2-fluoroethoxy)quinolin-2-yl, resp.] and [18F]20a [II: R1 = 3-(2-fluoroethoxy)quinolin-2-yl]. MicroPET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equil. kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington's disease and schizophrenia.328Bajjalieh, S. M.; Peterson, K.; Linial, M.; Scheller, R. H. Brain contains two forms of synaptic vesicle protein 2. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 2150– 2154, DOI: 10.1073/pnas.90.6.2150[Crossref], [PubMed], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXisFWqsrk%253D&md5=6b798d3ff7379b63676c14888f7737f0Brain contains two forms of synaptic vesicle protein 2Bajjalieh, Sandra M.; Peterson, Karen; Linial, Michal; Scheller, Richard H.Proceedings of the National Academy of Sciences of the United States of America (1993), 90 (6), 2150-4CODEN: PNASA6; ISSN:0027-8424.To det. whether synaptic vesicle protein 2 (SV2) is a member of a family of vesicular proteins, the SV2 clone was used to screen for similar cDNAs in rat brain. The authors characterized 42 clones, 25 of which encode SV2 and 4 of which encode a protein, SV2B, that is 65% identical and 78% similar to SV2. The protein encoded by the SV2B cDNA is recognized by the monoclonal antibody that defines the SV2 protein. When SV2B is expressed in COS cells, antibody labeling is reticular in nature, suggesting that SV2B, like SV2 (hence, SV2A), is segregated to intracellular membranes. The expression of SV2B is limited to neural tissue. While both forms of SV2 are expressed in all brain regions, SV2B is expressed at highest levels in the cortex and hippocampus, whereas the highest level of expression of SV2A is in subcortical regions. Therefore, the SV2 proteins, like other characterized synaptic vesicle proteins, comprise a small gene family.329Janz, R.; Südhof, T. C. SV2C is a synaptic vesicle protein with an unusually restricted localization: Anatomy of a synaptic vesicle protein family. Neuroscience 1999, 94, 1279– 1290, DOI: 10.1016/S0306-4522(99)00370-X[Crossref], [PubMed], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXotVGjtbc%253D&md5=5dcd49821be0a2b46658691884f5ffd0SV2C is a synaptic vesicle protein with an unusually restricted localization: anatomy of a synaptic vesicle protein familyJanz, R.; Sudhof, T. C.Neuroscience (Oxford) (1999), 94 (4), 1279-1290CODEN: NRSCDN; ISSN:0306-4522. (Elsevier Science Ltd.)The authors describe here the identification and mol. characterization of a new brain protein that they named SV2C because it is homologous to the synaptic vesicle proteins, SV2A and SV2B, and because it is also recognized by the monoclonal SV2 antibody that led to the initial discovery of SV2A and SV2B. SV2C is more closely related to SV2A (62% identity) than to SV2B (57% identity), and contains 12 transmembrane regions similar to these proteins. To characterize SV2C and compare its properties and localization with those of SV2A and SV2B, the authors raised an SV2C-specific antibody. Using this antibody, the authors show that SV2C is an N-glycosylated protein that is concd. on small synaptic vesicles; in addn., it is found on microvesicles in adrenal chromaffin cells. The authors evaluated the relative localization of the 3 SV2 isoforms by staining rat brain sections with antibodies specific for SV2A, SV2B, and SV2C. Anal. of the resulting staining patterns confirmed previous conclusions that SV2A is ubiquitously expressed in virtually all synapses. SV2B, although more restricted in distribution, was also found in a wide variety of synapses throughout the brain. In striking contrast to this general localization and to similarly wide distributions of other synaptic vesicle proteins, SV2C was obsd. only in few brain areas. High levels of SV2C were found primarily in phylogenetically old brain regions such as the pallidum, the substantia nigra, the midbrain, the brainstem, and the olfactory bulb. SV2C was undetectable in the cerebral cortex and the hippocampus, and found at low levels in the cerebellar cortex. The data suggest that closely related members of a synaptic vesicle protein family can either have very general (SV2A) or restricted distributions (SV2C), possibly in order to allow specialization in the regulation of the expression or of the function of these abundant synaptic vesicle proteins.330Heurling, K.; Ashton, N. J.; Leuzy, A.; Zimmer, E. R.; Blennow, K.; Zetterberg, H.; Eriksson, J.; Lubberink, M.; Schöll, M. Synaptic vesicle protein 2A as a potential biomarker in synaptopathies. Mol. Cell. Neurosci. 2019, 97, 34– 42, DOI: 10.1016/j.mcn.2019.02.001[Crossref], [PubMed], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXks1eisLw%253D&md5=2f4ffa7bf68dbc4a6d93a57956f0f107Synaptic vesicle protein 2A as a potential biomarker in synaptopathiesHeurling, Kerstin; Ashton, Nicholas J.; Leuzy, Antoine; Zimmer, Eduardo R.; Blennow, Kaj; Zetterberg, Henrik; Eriksson, Jonas; Lubberink, Mark; Schoell, MichaelMolecular and Cellular Neuroscience (2019), 97 (), 34-42CODEN: MOCNED; ISSN:1044-7431. (Elsevier B.V.)A review. Measuring synaptic d. in vivo using positron emission tomog. (PET) imaging-based biomarkers targeting the synaptic vesicle protein 2A (SV2A) has received much attention recently due to its potential research and clin. applications in synaptopathies, including neurodegenerative and psychiatric diseases. Fluid-based biomarkers in proteinopathies have previously been suggested to provide information on pathol. and disease status that is complementary to PET-based measures, and the same can be hypothesized with respect to SV2A. This review provides an overview of the current state of SV2A PET imaging as a biomarker of synaptic d., the potential role of fluid-based biomarkers for SV2A, and related future perspectives.331Mendoza-Torreblanca, J. G.; Vanoye-Carlo, A.; Phillips-Farfán, B. V.; Carmona-Aparicio, L.; Gómez-Lira, G. Synaptic vesicle protein 2A: Basic facts and role in synaptic function. Eur. J. Neurosci. 2013, 38, 3529– 3539, DOI: 10.1111/ejn.12360[Crossref], [PubMed], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252FjsFShtg%253D%253D&md5=e0c218b1342f09fb69110d8beb93cfd8Synaptic vesicle protein 2A: basic facts and role in synaptic functionMendoza-Torreblanca Julieta Griselda; Vanoye-Carlo America; Phillips-Farfan Bryan Victor; Carmona-Aparicio Liliana; Gomez-Lira GiselaThe European journal of neuroscience (2013), 38 (11), 3529-39 ISSN:.In recent years, there has been considerable interest in determining the function of synaptic vesicle protein 2A and its role as a target for antiepileptic drugs. Although it is known that synaptic vesicle protein 2A is involved in normal synaptic vesicle function, its participation in synaptic vesicle cycling and neurotransmitter release in normal and pathological conditions is unclear. However, the experimental evidence suggests that synaptic vesicle protein 2A could be a vesicular transporter, regulate synaptic exocytosis as a gel matrix, or modulate synaptotagmin-1 activity. This review describes and discusses the participation of synaptic vesicle protein 2A in synaptic modulation in normal and pathological conditions.332Koole, M.; van Aalst, J.; Devrome, M.; Mertens, N.; Serdons, K.; Lacroix, B.; Mercier, J.; Sciberras, D.; Maguire, P.; Van Laere, K. Quantifying SV2A density and drug occupancy in the human brain using [11C]UCB-J PET imaging and subcortical white matter as reference tissue. Eur. J. Nucl. Med. Mol. Imaging 2019, 46, 396– 406, DOI: 10.1007/s00259-018-4119-8[Crossref], [PubMed], [CAS], Google Scholar332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFCku7bM&md5=865e8f1e0b40ffa9f924be7871a300a0Quantifying SV2A density and drug occupancy in the human brain using [11C]UCB-J PET imaging and subcortical white matter as reference tissueKoole, Michel; van Aalst, June; Devrome, Martijn; Mertens, Nathalie; Serdons, Kim; Lacroix, Brigitte; Mercier, Joel; Sciberras, David; Maguire, Paul; Van Laere, KoenEuropean Journal of Nuclear Medicine and Molecular Imaging (2019), 46 (2), 396-406CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: A [11C]UCB-J blocking study was performed in healthy volunteers to validate simplified, non-invasive measures for quantifying presynaptic SV2A expression using subcortical white matter as ref. tissue. Methods: Ninety minutes dynamic [11C]UCB-J PET scanning with arterial blood sampling was performed in 10 healthy volunteers (8 M/2F; age 27.6 ± 10.0 yrs), before and after administration of a novel chem. entity with selective affinity for SV2A. The centrum semi-ovale (SO) was validated as ref. region by comparing baseline and post treatment distribution vol. (VT). Using SO as ref. tissue, Binding Potential (BPSO) using a Simplified Ref. Tissue Model (SRTM, down to 60 min acquisition) and Standardized Uptake Value Ratios (60-90 min post injection - SUVRSO,60-90min) were compared with regional distribution vol. ratios (DVR). Next, SV2A occupancy values based on SRTM BPSO and SUVRSO,60-90min were compared to occupancy ests. using regional VT values and a Lassen plot. Results: After pretreatment, regional VT values were reduced significantly except for SO. Highly significant correlations were found between DVR, SRTM BPSO and SUVRSO,60-90min. Compared to DVR, baseline SRTM BPSO showed a small bias (≤ 6.1%) with lower precision for shorter acquisition times, while SUVRSO,60-90min showed 3.5% bias with similar precision. Differences between SV2A occupancy values based on SUVRSO,60-90min and occupancy ests. using VT and a Lassen plot were small but significant, while negligible bias was found for SRTM based occupancy ests. (at least 70 min acquisition). Conclusion: This [11C]UCB-J blocking study validated SO as a suitable ref. region for non-invasive quantification of SV2A availability and drug occupancy in the human brain. Accurate quantification can be achieved by using either SUVRSO,60-90min with a 60-90 min PET acquisition or SRTM BPSOwith at least 70 min dynamic PET acquisition.333Holmes, S. E.; Scheinost, D.; Finnema, S. J.; Naganawa, M.; Davis, M. T.; DellaGioia, N.; Nabulsi, N.; Matuskey, D.; Angarita, G. A.; Pietrzak, R. H.; Duman, R. S.; Sanacora, G.; Krystal, J. H.; Carson, R. E.; Esterlis, I. Lower synaptic density is associated with depression severity and network alterations. Nat. Commun. 2019, 10, 1529, DOI: 10.1038/s41467-019-09562-7[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M%252FhvVektQ%253D%253D&md5=d2e910216349cc49de47a600f14aae90Lower synaptic density is associated with depression severity and network alterationsHolmes Sophie E; Finnema Sjoerd J; Davis Margaret T; DellaGioia Nicole; Matuskey David; Angarita Gustavo A; Pietrzak Robert H; Duman Ronald S; Sanacora Gerard; Krystal John H; Esterlis Irina; Scheinost Dustin; Naganawa Mika; Nabulsi Nabeel; Matuskey David; Carson Richard E; Pietrzak Robert H; Krystal John H; Esterlis IrinaNature communications (2019), 10 (1), 1529 ISSN:.Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand [(11)C]UCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.334Finnema, S. J.; Nabulsi, N. B.; Eid, T.; Detyniecki, K.; Lin, S.; Chen, M.-K.; Dhaher, R.; Matuskey, D.; Baum, E.; Holden, D.; Spencer, D. D.; Mercier, J.; Hannestad, J.; Huang, Y.; Carson, R. E. Imaging synaptic density in the living human brain. Sci. Transl. Med. 2016, 8, 348ra96, DOI: 10.1126/scitranslmed.aaf6667335Chen, M.-K.; Mecca, A. P.; Naganawa, M.; Finnema, S. J.; Toyonaga, T.; Lin, S.; Najafzadeh, S.; Ropchan, J.; Lu, Y.; McDonald, J. W.; Michalak, H. R.; Nabulsi, N. B.; Arnsten, A. F. T.; Huang, Y.; Carson, R. E.; van Dyck, C. H. Assessing synaptic density in alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018, 75, 1215– 1224, DOI: 10.1001/jamaneurol.2018.1836[Crossref], [PubMed], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252Fosl2kuw%253D%253D&md5=2909e059f92d8b546f57b1eb7d730a4aAssessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic ImagingChen Ming-Kai; Naganawa Mika; Finnema Sjoerd J; Toyonaga Takuya; Lin Shu-Fei; Najafzadeh Soheila; Ropchan Jim; Lu Yihuan; Nabulsi Nabeel B; Huang Yiyun; Carson Richard E; Mecca Adam P; McDonald Julia W; Michalak Hannah R; Arnsten Amy F T; van Dyck Christopher HJAMA neurology (2018), 75 (10), 1215-1224 ISSN:.Importance: Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density. Objective: To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging. Design, Setting, and Participants: This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as 11C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B (11C-PiB) for β-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation. Main Outcomes and Measures: Outcomes were 11C-UCB-J-specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal. Results: Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] β-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] β-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by 11C-UCB-J-PET BPND (cognitively normal participants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BPND was correlated with a composite episodic memory score in the overall sample (R = 0.56; P = .01). Conclusions and Relevance: To our knowledge, this is the first study to investigate synaptic density in vivo in AD using 11C-UCB-J-PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses.336Bahri, M. A.; Plenevaux, A.; Aerts, J.; Bastin, C.; Becker, G.; Mercier, J.; Valade, A.; Buchanan, T.; Mestdagh, N.; Ledoux, D.; Seret, A.; Luxen, A.; Salmon, E. Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H. Alzheimer's Dementia 2017, 3, 481– 486, DOI: 10.1016/j.trci.2017.08.004[Crossref], [CAS], Google Scholar336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7pvVGmtw%253D%253D&md5=a0513a751289295cb03597c806ea75dcMeasuring brain synaptic vesicle protein 2A with positron emission tomography and [(18)F]UCB-HBahri Mohamed Ali; Plenevaux Alain; Aerts Joel; Bastin Christine; Becker Guillaume; Seret Alain; Luxen Andre; Salmon Eric; Mercier Joel; Valade Anne; Buchanan Tim; Mestdagh Nathalie; Ledoux DidierAlzheimer's & dementia (New York, N. Y.) (2017), 3 (4), 481-486 ISSN:.Introduction: Brain distribution of synaptic vesicle protein 2A was measured with fluorine-18 UCB-H ([(18)F]UCB-H) and positron emission tomography (PET). Methods: Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume. Results: [(18)F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship. Discussion: The cerebral distribution of [(18)F]UCB-H is similar to that recently observed with carbon-11 UCB-J ([(11)C]UCB-J). An accurate [(18)F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging.337Bertoglio, D.; Verhaeghe, J.; Miranda, A.; Kertesz, I.; Cybulska, K.; Korat, Š.; Wyffels, L.; Stroobants, S.; Mrzljak, L.; Dominguez, C.; Liu, L.; Skinbjerg, M.; Munoz-Sanjuan, I.; Staelens, S. Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice. J. Cereb. Blood Flow Metab. 2020, 40, 1351– 1362, DOI: 10.1177/0271678X19864081[Crossref], [PubMed], [CAS], Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsVOku7w%253D&md5=87ec9da23705bc19ca4bd04d60afd811Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in miceBertoglio, Daniele; Verhaeghe, Jeroen; Miranda, Alan; Kertesz, Istvan; Cybulska, Klaudia; Korat, Spela; Wyffels, Leonie; Stroobants, Sigrid; Mrzljak, Ladislav; Dominguez, Celia; Liu, Longbin; Skinbjerg, Mette; Munoz-Sanjuan, Ignacio; Staelens, StevenJournal of Cerebral Blood Flow & Metabolism (2020), 40 (6), 1351-1362CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)This study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examd. kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metab. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT(IDIF) values estd. with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K1(IDIF). A scan duration of 60 min was sufficient for reliable VT(IDIF) and K1(IDIF) estns. In vivo metab. of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic d. in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.338Ribeiro, F. M.; Hamilton, A.; Doria, J. G.; Guimaraes, I. M.; Cregan, S. P.; Ferguson, S. S. Metabotropic glutamate receptor 5 as a potential therapeutic target in Huntington’s disease. Expert Opin. Ther. Targets 2014, 18, 1293– 1304, DOI: 10.1517/14728222.2014.948419[Crossref], [PubMed], [CAS], Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslOhu7nE&md5=2f98555f677157f208cc8a1d1c049ef4Metabotropic glutamate receptor 5 as a potential therapeutic target in Huntington's diseaseRibeiro, Fabiola M.; Hamilton, Alison; Doria, Juliana G.; Guimaraes, Isabella M.; Cregan, Sean P.; Ferguson, Stephen SGExpert Opinion on Therapeutic Targets (2014), 18 (11), 1293-1304CODEN: EOTTAO; ISSN:1472-8222. (Informa Healthcare)Introduction: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein, which underlies the loss of striatal and cortical neurons. Glutamate has been implicated in a no. of neurodegenerative diseases, and several studies suggest that the metabotropic glutamate receptor 5 (mGluR5) may represent a target for the treatment of HD. Areas covered: The main goal of this review is to discuss the current data in the literature regarding the role of mGluR5 in HD and evaluate the potential of mGluR5 as a therapeutic target for the treatment of HD. MGluR5 is highly expressed in the brain regions affected in HD and is involved in movement control. Moreover, mGluR5 interacts with htt and mutated htt profoundly affects mGluR5 signaling. However, mGluR5 stimulation can activate both neuroprotective and neurotoxic signaling pathways, depending on the context of activation. Expert opinion: Although the data published so far strongly indicate that mGluR5 plays a major role in HD-assocd. neurodegeneration, htt aggregation and motor symptoms, it is not clear whether mGluR5 stimulation can diminish or intensify neuronal cell loss and HD progression. Thus, future expts. will be necessary to further investigate the outcome of drugs acting on mGluR5 for the treatment of neurodegenerative diseases.339Bertoglio, D.; Kosten, L.; Verhaeghe, J.; Thomae, D.; Wyffels, L.; Stroobants, S.; Wityak, J.; Dominguez, C.; Mrzljak, L.; Staelens, S. Longitudinal characterization of mGluR5 using 11C-ABP688 PET imaging in the Q175 mouse model of Huntington disease. J. Nucl. Med. 2018, 59, 1722– 1727, DOI: 10.2967/jnumed.118.210658[Crossref], [PubMed], [CAS], Google Scholar339https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXktVajs78%253D&md5=ddaeb6736b0f2c2119a03b738b3d3fd0Longitudinal characterization of mGluR5 using 11C-ABP688 PET imaging in the Q175 mouse model of Huntington diseaseBertoglio, Daniele; Kosten, Lauren; Verhaeghe, Jeroen; Thomae, David; Wyffels, Leonie; Stroobants, Sigrid; Wityak, John; Dominguez, Celia; Mrzljak, Ladislav; Staelens, StevenJournal of Nuclear Medicine (2018), 59 (11), 1722-1728CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Metabotropic glutamate receptor 5 (mGluR5) represents a potential therapeutic target for Huntington disease. Using 11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for mGluR5, we aimed to longitudinally characterize in vivo changes in mGluR5 by means of PET imaging in the Q175 mouse model of Huntington disease. Methods: 11C-ABP688 PET imaging, followed by a CT scan, was performed on 18 heterozygous mice and 18 wild-type (WT) littermates at 3 different time points (6, 9, and 13 mo old). 11C-ABP688 nondisplaceable binding potential (BPND) was calcd. for each time point in striatum and cortex using the cerebellum as the ref. region. In addn., voxel-based statistical parametric mapping (SPM) anal. was performed on BPND images. Postmortem validation of mGluR5 level and neuronal d. was performed on the mice at 6 mo old. Results: The 11C-ABP688 BPND of heterozygous animals was significantly reduced at all time points in the striatum (-13.1%, -13.5%, and -14.2% at 6, 9, and 13 mo, resp.; P < 0.001 for all) and in the cortex (-9.8%, -10.2%, and -10.6%, resp.; P < 0.01 for all), when compared with WT animals. Longitudinal changes in 11C-ABP688 BPND were also found in heterozygous mice, showing a redn. at 13 mo compared with 6 mo (-10.4%, P < 0.05). SPM anal. confirmed reduced BPND in heterozygous compared with WT mice, as well as a time-related decline in 11C-ABP688 binding in the striatum of heterozygous mice. Postmortem anal. confirmed a mGluR5 decrease in both striatum (-36.6%; P < 0.01) and cortex (-16.6%; P < 0.05) in heterozygous mice, whereas no difference in neuronal d. was found. Conclusion: In vivo imaging of mGluR5 using 11C-ABP688 PET/CT revealed a marked redn. in ligand binding in the striatum and cortex of heterozygous mice, compared with WT mice, as well as a temporal decline. This study suggests that 11C-ABP688 PET imaging is a potential biomarker to monitor the progression of, and therapeutic strategies for, Huntington disease.340Fang, X. T.; Eriksson, J.; Antoni, G.; Yngve, U.; Cato, L.; Lannfelt, L.; Sehlin, D.; Syvänen, S. Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [11C]ABP688 PET imaging and ex vivo immunoblotting. Neuropharmacology 2017, 113, 293– 300, DOI: 10.1016/j.neuropharm.2016.10.009[Crossref], [PubMed], [CAS], Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslegsL%252FF&md5=9a6d01f4fb88a58089691d1fcffd0d5bBrain mGluR5 in mice with amyloid beta pathology studied with in vivo [11C]ABP688 PET imaging and ex vivo immunoblottingFang, Xiaotian T.; Eriksson, Jonas; Antoni, Gunnar; Yngve, Ulrika; Cato, Linda; Lannfelt, Lars; Sehlin, Dag; Syvaenen, StinaNeuropharmacology (2017), 113 (Part_A), 293-300CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insol. plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [11C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathol. progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning. In order to convey these neurotoxic effects, Aβo requires interaction with the metabotropic glutamate 5 receptor (mGluR5). The aim was to investigate in vivo mGluR5 changes in an Aβ pathol. model using PET. Wild type C57/BL6 (wt) and AβPP transgenic mice (tg-ArcSwe), 4, 8, and 16 mo old, were PET scanned with [11C]ABP688, which is highly specific to mGluR5, to investigate changes in mGluR5. Mouse brains were extd. postscan and mGluR5 and Aβ protofibril levels were assessed with immunoblotting and ELISA resp. Receptor-dense brain regions (hippocampus, thalamus, and striatum) displayed higher [11C]ABP688 concns. corresponding to mGluR5 expression pattern. Mice had similar uptake levels of [11C]ABP688 regardless of genotype or age. Immunoblotting revealed general decline in mGluR5 expression and elevated levels of mGluR5 in 16 mo old tg-ArcSwe compared with wt mice. [11C]ABP688 could visualize mGluR5 in the mouse brain. In conclusion, mGluR5 levels were found to decrease with age and tended to be higher in tg-ArcSwe compared with wt mice, however these changes could not be quantified with PET.341Ametamey, S. M.; Kessler, L. J.; Honer, M.; Wyss, M. T.; Buck, A.; Hintermann, S.; Auberson, Y. P.; Gasparini, F.; Schubiger, P. A. Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J. Nucl. Med. 2006, 47, 698– 705[PubMed], [CAS], Google Scholar341https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkt1Oisr8%253D&md5=a335f1d6e9bc6c22d20bdf1987ae7bd7Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5Ametamey, Simon M.; Kessler, Lea J.; Honer, Michael; Wyss, Matthias T.; Buck, Alfred; Hintermann, Samuel; Auberson, Yves P.; Gasparini, Fabrizio; Schubiger, Pius A.Journal of Nuclear Medicine (2006), 47 (4), 698-705CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. ABP688 was radiolabeled with 11C by reacting 11C-Me iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime). The affinity of 11C-ABP688 for mGluR5 was detd. by Scatchard anal. using rat whole-brain membranes (without cerebellum). Ex vivo autoradiog., biodistribution, and PET studies with 11C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. The overall synthesis time was 45-50 min from the end of radionuclide prodn. 11C-ABP688 was obtained in good radiochem. yield (35% ± 8%, n = 17, decay cor.), and the specific radioactivity was 150±50 GBq/μmol (n = 17) at the end of the synthesis. Scatchard anal. revealed a single high-affinity binding site with a dissocn. const. of 1.7 ± 0.2 nmol/L and a max. no. of binding sites of 231 ±18 fmol/mg of protein. Ex vivo autoradiog. in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of 11C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of 11C-ABP688 was obsd. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of 11C-ABP688 binding to mGluR5. 11C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.342Akkus, F.; Mihov, Y.; Treyer, V.; Ametamey, S. M.; Johayem, A.; Senn, S.; Rösner, S.; Buck, A.; Hasler, G. Metabotropic glutamate receptor 5 binding in male patients with alcohol use disorder. Transl. Psychiatry 2018, 8, 17, DOI: 10.1038/s41398-017-0066-6[Crossref], [PubMed], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MzptFWlug%253D%253D&md5=e6dc3a4eeac0efbf607c5ceb142f9342Metabotropic glutamate receptor 5 binding in male patients with alcohol use disorderAkkus Funda; Mihov Yoan; Hasler Gregor; Treyer Valerie; Johayem Anass; Buck Alfred; Ametamey Simon M; Senn Smeralda; Rosner SusanneTranslational psychiatry (2018), 8 (1), 17 ISSN:.Glutamate signaling plays a major role in addiction. Preclinical research strongly suggests an implication of G-protein-coupled metabotropic glutamate receptor subtype 5 (mGluR5) in nicotine addiction and alcohol use disorder. In humans, smoking is related to a global reduction in mGluR5 availability. In the present study, we investigated mGluR5 in vivo in patients with alcohol use disorder without the confounding effects of smoking. A total of 14 male subjects with alcohol use disorder and at least a 25-day abstinence and 14 matched male non-smoking healthy controls were included in the study. We employed positron emission tomography (PET) with the mGluR5-specific radiotracer [11C]ABP688, using a bolus/infusion protocol. We found increased mGluR5 DVR in several regions within the temporal lobe in patients, as compared to controls. The largest between-group difference was in the amygdala. There was a marked positive relation between mGluR5 DVR in the anterior cingulate and mGluR5 DVR in the orbitofrontal cortex in patients, but not in controls. In patients, lower temptation to drink was related to higher amygdala mGluR5 DVR. We did not find altered mGluR5 DVR in the basal ganglia of subjects recovering from alcohol use disorder. In conclusion, our study provides clinical evidence for altered mGluR5 signaling in the amygdala in alcohol use disorder. This alteration was associated with the temptation to drink. In addition, this study suggests abnormal mGluR5 signaling in a network underlying reward-related behavioral flexibility. These findings strengthen the case for pharmacological agents acting on mGluR5 as promising candidates for the treatment of alcohol use disorder.343Treyer, V.; Gietl, A. F.; Suliman, H.; Gruber, E.; Meyer, R.; Buchmann, A.; Johayem, A.; Unschuld, P. G.; Nitsch, R. M.; Buck, A.; Ametamey, S. M.; Hock, C. Reduced uptake of [11C]-ABP688, a PET tracer for metabolic glutamate receptor 5 in hippocampus and amygdala in Alzheimer’s dementia. Brain Behav. 2020, 10, e01632 DOI: 10.1002/brb3.1632344Ametamey, S. M.; Treyer, V.; Streffer, J.; Wyss, M. T.; Schmidt, M.; Blagoev, M.; Hintermann, S.; Auberson, Y.; Gasparini, F.; Fischer, U. C.; Buck, A. Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688. J. Nucl. Med. 2007, 48, 247– 252[PubMed], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVKmsb0%253D&md5=be3ec54c117f3789e4482b1e138568b3Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688Ametamey, Simon M.; Treyer, Valerie; Streffer, Johannes; Wyss, Matthias T.; Schmidt, Mark; Blagoev, Milen; Hintermann, Samuel; Auberson, Yves; Gasparini, Fabrizio; Fischer, Uta C.; Buck, AlfredJournal of Nuclear Medicine (2007), 48 (2), 247-252CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime (11C-ABP688), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: Six healthy male volunteers (mean age, 25 y; range, 21-33 y) were studied. Brain perfusion (15O-H2O) was measured immediately before each 11C-ABP688 PET scan. For anat. coregistration, T1-weighted MRI was performed on each subject. Arterial blood samples for the detn. of the arterial input curve were obtained at predefined time points, and 11C-ABP688 uptake was assessed quant. using a 2-tissue-compartment model. Results: An initial rapid uptake of radioactivity followed by a gradual clearance from all examd. brain regions was obsd. Relatively high radioactivity concns. were obsd. in mGluR5-rich brain regions such as the anterior cingulate, medial temporal lobe, amygdala, caudate, and putamen, whereas radioactivity uptake in the cerebellum and white matter, regions known to contain low densities of mGluR5, was low. Specific distribution vol. as an outcome measure of mGluR5 d. in the various brain regions ranged from 5.45 ± 1.47 (anterior cingulate) to 1.91 ± 0.32 (cerebellum), and the rank order of the corresponding specific distribution vols. of 11C-ABP688 in cortical regions was temporal > frontal > occipital > parietal. The metab. of 11C-ABP688 in plasma was rapid; at 60 min after injection, 25% ± 0.03% of radioactivity measured in the plasma of healthy volunteers was intact parent compd. Conclusion: The results of these studies indicate that 11C-ABP688 has suitable characteristics and is a promising PET ligand for imaging mGluR5 distribution in humans. Furthermore, it could be of great value for the selection of appropriate doses of clin. relevant candidate drugs that bind to mGluR5 and for PET studies of patients with psychiatric and neurol. disorders.345Paoletti, P.; Bellone, C.; Zhou, Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 2013, 14, 383– 400, DOI: 10.1038/nrn3504[Crossref], [PubMed], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvVSit7Y%253D&md5=f69790da360242d491bf1a5eb146613dNMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and diseasePaoletti, Pierre; Bellone, Camilla; Zhou, QiangNature Reviews Neuroscience (2013), 14 (6), 383-400CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)A review. NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit compn. of NMDARs is plastic, resulting in a large no. of receptor subtypes. As each receptor subtype has distinct biophys., pharmacol. and signaling properties, there is great interest in detg. whether individual subtypes carry out specific functions in the CNS in both normal and pathol. conditions. Here, we review the effects of subunit compn. on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.346Haider, A.; Herde, A. M.; Krämer, S. D.; Varisco, J.; Keller, C.; Frauenknecht, K.; Auberson, Y. P.; Temme, L.; Robaa, D.; Sippl, W.; Schibli, R.; Wünsch, B.; Mu, L.; Ametamey, S. M. Preclinical evaluation of benzazepine-based PET radioligands (R)- and (S)-11C-Me-NB1 reveals distinct enantiomeric binding patterns and a tightrope walk between GluN2B- and σ1-receptor-targeted PET imaging. J. Nucl. Med. 2019, 60, 1167– 1173, DOI: 10.2967/jnumed.118.221051[Crossref], [PubMed], [CAS], Google Scholar346https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsF2mtA%253D%253D&md5=e32447d3f8fc88a2625b278fc4849001Preclinical evaluation of benzazepine-based PET radioligands (R)- and (S)-11C-Me-NB1 reveals distinct enantiomeric binding patterns and a tightrope Walk Between GluN2B- and σ 1-receptor-targeted PET imagingHaider, Ahmed; Herde, Adrienne Muller; Kramer, Stefanie D.; Varisco, Jasmine; Keller, Claudia; Frauenknecht, Katrin; Auberson, Yves P.; Temme, Louisa; Robaa, Dina; Sippl, Wolfgang; Schibli, Roger; Wunsch, Bernhard; Mu, Linjing; Ametamey, Simon M.Journal of Nuclear Medicine (2019), 60 (8), 1167-1173CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)The study aims to investigate the performance characteristics of the enantiomers of 11C-Me-NB1, a recently reported PET imaging probe that targets the GluN2B subunit of N-methyl-D-aspartate (NMDA) receptors. Ref. compd. Me-NB1 (inhibition const. for hGluN1/GluN2B, 5.4 nM) and the phenolic precursor were prepd. via multistep synthesis. Following chiral resoln. by high-performance liq. chromatog., enantiopure precursor compds., (R)-NB1 and (S)-NB1, were labeled with 11C and validated in rodents using in vitro/ex vivo autoradiog., PET expts., and dose-response studies. To illustrate the translational relevance, (R)-11C-Me-NB1 was validated in autoradiog. studies using postmortem human GluN2B-rich cortical and GluN2B-deficient cerebellar brain slices. To det. target engagement, receptor occupancy was assessed at different plasma concns. of CP101,606, a GluN2B receptor antagonist. The radiosynthesis of (R)- and (S)-11C-Me-NB1 was accomplished in 42% ± 9% (decay-cor.) radiochem. yields. Molar activity ranged from 40 to 336 GBq/μmol, and an excellent radiochem. purity of greater than 99% was achieved. Although (R)-11C-Me-NB1 displayed heterogeneous accumulation with high selectivity for the GluN2B-rich forebrain, (S)-11nt brain, (R)-11C-Me-NB1 showed in postmortem human brain tissues higher binding in the cortex than in the cerebellum. Coincubation of the GluN2B-antagonist CERC-301 (1 μM) reduced cortical but not cerebellar binding, demonstrating the specificity of (R)-11C-Me-NB1 binding to the human GluN2B-contg. NMDA receptor. In vivo specificity of (R)-11CMe-NB1 in the GluN2B-expressing cortex, striatum, thalamus, and hippocampus was demonstrated by PET imaging in rodents. Applying GluN2B-antagonist eliprodil, an evident dose-response behavior was obsd. with (R)-11C-Me-NB1 but not with (S)-11CMe-NB1. Our findings further underline the tightrope walk between GluN2B- and σ1-receptor-targeted imaging, illustrated by the entirely different receptor binding behavior of the 2 radioligand enantiomers. (R)-11C-Me-NB1 is a highly selective and specific PET radioligand for imaging the GluN2B subunit of the NMDA receptor. The entirely different receptor binding behavior of (R)-11C-Me-NB1 and (S)-11C-Me-NB1 raises awareness of a delicate balance that is underlying the selective targeting of either GluN2Bcarrying NMDA or σ1-receptors.347Krämer, S. D.; Betzel, T.; Mu, L.; Haider, A.; Herde, A. M.; Boninsegni, A. K.; Keller, C.; Szermerski, M.; Schibli, R.; Wünsch, B.; Ametamey, S. M. Evaluation of 11 C-Me-NB1 as a potential PET radioligand for measuring GluN2B-containing NMDA receptors, drug occupancy, and receptor cross talk. J. Nucl. Med. 2018, 59, 698– 703, DOI: 10.2967/jnumed.117.200451[Crossref], [PubMed], [CAS], Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlKgtrzJ&md5=7a65e25cb9ca56581cb90d9b9d2d53a9Evaluation of 11C-Me-NB1 as a potential PET radioligand for measuring GluN2B-containing NMDA receptors, drug occupancy, and receptor cross talkKramer, Stefanie D.; Betzel, Thomas; Mu, Linjing; Haider, Ahmed; Herde, Adrienne Muller; Boninsegni, Anna K.; Keller, Claudia; Szermerski, Marina; Schibli, Roger; Wunsch, Bernhard; Ametamey, Simon M.Journal of Nuclear Medicine (2018), 59 (4), 698-703CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Clin. and preclin. research with modulators at the N-methyl-D- aspartate (NMDA) receptor GluN2B N-terminal domain (NTD) aims for the treatment of various neurol. diseases. The interpreta- tion of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of potential drugs. We have developed 11C-Me-NB1 as a PET tracer for imaging GluN1/GluN2B-contg. NMDA receptors and used it to in- vestigate in rats the dose-dependent receptor occupancy of eli- prodil, a GluN2B NTD modulator. 11C-Me-NB1 was synthesized and characterized by in vitro displacement binding ex- periments with rat brain membranes, in vitro autoradiog., and blocking and displacement expts. by PET and PET kinetic modeling. Receptor occupancy by eliprodil was studied by PET with 11C-Me-NB1. 11C-Me-NB1 was synthesized at 290 ± 90 GBq/mmol molar activity, 7.4 ± 1.9 GBq total activity at the end of synthesis (n = 17), and more than 99% radiochem. purity. 11C- Me-NB1 binding in rat brain was blocked in vitro and in vivo by the NTD modulators Ro-25-6981 and eliprodil. Half-maximal receptor occupancy by eliprodil occurred at 1.5 mg/kg. At 1 mg/kg of elipro- dil, a dose with reported neuroprotective effects, more than 99.5% of binding sites were occupied. In vitro, 11C-Me-NB1 binding was independent of the s-1 receptor (Sigma1R), and the Sigma1R ago- nist (+)-pentazocine did not compete for high-affinity binding. In vivo, a 2.5 mg/kg dose of (+)-pentazocine abolished 11C-Me- NB1-specific binding, indicating an indirect effect of Sigma1R on 11C-Me-NB1 binding. 11C-Me-NB1 is suitable for the in vivo imaging of NMDA GluN1/GluN2B receptors and the assess- ment of receptor occupancy by NTD modulators. GluN1/GluN2B NMDA receptors are fully occupied at neuroprotective doses of eliprodil. Furthermore, 11C-Me-NB1 enables imaging of GluN1/GluN2B NMDA receptor cross talk.348Weeks, R. A.; Cunningham, V. J.; Piccini, P.; Waters, S.; Harding, A. E.; Brooks, D. J. 11C-diprenorphine binding in Huntington’s disease: A comparison of region of interest analysis with statistical parametric mapping. J. Cereb. Blood Flow Metab. 1997, 17, 943– 949, DOI: 10.1097/00004647-199709000-00003[Crossref], [PubMed], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmsVagtbk%253D&md5=eb80135e5fc3ef405766c7a219b02ee011C-diprenorphine binding in Huntington's disease: a comparison of region of interest analysis with statistical parametric mappingWeeks, Robert A.; Cunningham, Vincent J.; Piccini, Paola; Waters, Simon; Harding, Anita E.; Brooks, David J.Journal of Cerebral Blood Flow and Metabolism (1997), 17 (9), 943-949CODEN: JCBMDN; ISSN:0271-678X. (Lippincott-Raven)We compare region of interest (ROI) anal. approaches with statistical parametric mapping (SPM) of 11C-diprenorphine positron emission tomog. findings in five patients with Huntington's disease (HD) and nine age-matched controls. The ROI were placed on caudate, putamen, and an occipital ref. area. Ratios of striatal-occipital uptake from averaged static images centered at 60 min showed a mean 20% redn. in caudate (P = 0.034) and 15% redn. in putamen (P = 0.095) receptor binding in the HD patients. Dynamic data from caudate and putamen ROI, together with a plasma tracer input function, were analyzed using spectral anal. to give regional impulse response functions. Regional data at 60 min after impulse showed a mean 29% decrease in caudate (P = 0.006) and 23% decrease in putamen (P = 0.029) opioid binding in the HD cohort. Parametric images of tracer binding also were produced with spectral anal. on a voxel basis. The images of the unit impulse response function at 60 min showed a mean 31% decrease in caudate (P = 0.005) and a 26% decrease in putamen binding (P = 0.011) in HD. The voxel-based parametric images were transformed into std. stereotactic space, and a between-group comparison (patient vs. controls) was performed with SPM. This approach revealed sym. decreases in caudate (peak 40% decrease, z score = 4.38) and putamen opioid binding (peak 24% decrease, z score = 4.686) with addnl. nonhypothesized changes in cingulate prefrontal, and thalamic areas. The significance and precision of changes measured with spectral anal. applied to dynamic data sets were superior to ROI-based ratio anal. on static images. The SPM replicated the striatal redns. in opioid binding in HD and detected addnl. nonpredicted changes. This study suggests that SPM is a valid alternative to conventional ROI anal. approaches for detg. binding changes with positron emission tomog. and may have advantages over region-based analyses in exploratory studies.349Talbot, P. S.; Narendran, R.; Butelman, E. R.; Huang, Y.; Ngo, K.; Slifstein, M.; Martinez, D.; Laruelle, M.; Hwang, D.-R. 11C-GR103545, a radiotracer for imaging kappa-opioid receptors in vivo with PET: Synthesis and evaluation in baboons. J. Nucl. Med. 2005, 46, 484– 494[PubMed], [CAS], Google Scholar349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXivVCgurY%253D&md5=ff4a001a2ea796bb654cc42dce977a2d11C-GR103545, a radiotracer for imaging κ-opioid receptors in vivo with PET: Synthesis and evaluation in baboonsTalbot, Peter S.; Narendran, Raj; Butelman, Eduardo R.; Huang, Yiyun; Ngo, Kim; Slifstein, Mark; Martinez, Diana; Laruelle, Marc; Hwang, Dah-RenJournal of Nuclear Medicine (2005), 46 (3), 484-494CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Brain κ-opioid receptors (ORs) may be involved in several pathol. conditions, such as addiction, psychosis, and seizures. (±)-4-Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a potent and selective κ-OR agonist. The (-)-isomer, GR103545, is the active enantiomer of GR89696. The aim of this study was to characterize the potential of 11C-GR103545 to image κ-OR in vivo with PET. Methods: Brain uptake of 11C-GR103545 was studied in baboons under control conditions and after blockade by naloxone (1 mg/kg i.v.). Uptake of the racemic 11C-GR89696 and of the inactive enantiomer (+)-11C-GR89696 was also evaluated. Regional total distribution vols. were derived using the arterial input function and a 2-tissue-compartment model. Results: 11C-GR103545 showed excellent brain penetration and uptake kinetics, with significant washout obsd. within the time frame of the PET expt. Naloxone pretreatment did not affect cerebellar total distribution vol. and reduced total distribution vol. in other regions to a level comparable to that in the cerebellum. The regional pattern of 11C-GR103545 binding potential was consistent with the distribution of κ-OR in primate brain, with highest levels obsd. in anterior cortical regions (prefrontal cortex and cingulate cortex) and striatum. In most regions, the specific-to-nonspecific equil. partition coeff. (V3'') ranged from 1 to 2, predicting reliable quantification. 11C-GR103545 V3'' values were approx. double the 11C-GR89696 V3'' values, whereas (+)-11C-GR89696 V3'' values were negligible, demonstrating the enantiomeric selectivity of the binding and the advantage of using the pure active enantiomer for PET studies. Conclusion: 11C-GR103545 is a promising PET radiotracer for imaging the κ-OR.350Frost, J. J. PET imaging of the opioid receptor: The early years. Nucl. Med. Biol. 2001, 28, 509– 513, DOI: 10.1016/S0969-8051(01)00221-9[Crossref], [PubMed], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksVGrsbc%253D&md5=b56c97f811687432a765b8b0f05378d9PET imaging of the opioid receptor: the early yearsFrost, J. J.Nuclear Medicine and Biology (2001), 28 (5), 509-513CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)A review with 18 refs. is given on the development of opioid receptor imaging in the human brain by positron tomog. Labeling of opiate receptors started with 3H-naloxone in vivo followed by 3H-diprenorphine and 3H-lofentanil. The 1st PET demonstration in humans used 11C-carfentanil.351Frost, J. J.; Wagner, H. N.; Dannals, R. F.; Ravert, H. T.; Links, J. M.; Wilson, A. A.; Burns, H. D.; Wong, D. F.; McPherson, R. W.; Rosenbaum, A. E.; Kuhar, M. J.; Snyder, S. H. Imaging opiate receptors in the human brain by positron tomography. Journal of Computer Assisted Tomography. 1985, 9, 231– 236, DOI: 10.1097/00004728-198503000-00001[Crossref], [PubMed], [CAS], Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M7jt1Shsw%253D%253D&md5=37046593b372b13385ae5ec953709fbbImaging opiate receptors in the human brain by positron tomographyFrost J J; Wagner H N Jr; Dannals R F; Ravert H T; Links J M; Wilson A A; Burns H D; Wong D F; McPherson R W; Rosenbaum A EJournal of computer assisted tomography (1985), 9 (2), 231-6 ISSN:0363-8715.Carfentanil is a potent, synthetic opiate that binds to mu opiate receptors with very high affinity (KI = 0.051 nM, 37 degrees C). In rat brain, carfentanil is 90 and 250 times more selective for mu opiate receptors compared with delta and kappa opiate receptors, respectively. Carbon-11-carfentanil was synthesized by reacting [11C]methyliodide with the carboxylic acid precursor of carfentanil. Carbon-11-carfentanil was injected intravenously in man and a baboon and the distribution of the radioactivity in the brain was monitored using positron emission tomography. High concentrations of radioactivity were observed in the basal ganglia and thalamus, intermediate concentrations in the frontal and parietal cerebral cortex, and low concentrations in the cerebellum and occipital cortex; this distribution corresponds to the known regional density of opiate receptors measured using in vitro techniques. This heterogeneous distribution could be abolished by pretreatment with naloxone (1 mg/kg), an opiate antagonist. The percent inhibition of binding by naloxone is approximately 90% in the caudate nucleus and medial thalamus for the period 30-60 min after injection; therefore, this method is associated with a high level of specific binding to opiate receptors compared with nonspecific binding sites. The ability to measure opiate receptors in vivo in man makes it possible to study a variety of neurologic and psychiatric disorders in which opiate receptors are thought to be abnormal and to study physiologic role of opiate receptors in the central nervous system.352Zubieta, J.-K.; Gorelick, D. A.; Stauffer, R.; Ravert, H. T.; Dannals, R. F.; Frost, J. J. Increased mu opioid receptor binding detected by PET in cocaine–dependent men is associated with cocaine craving. Nat. Med. 1996, 2, 1225– 1229, DOI: 10.1038/nm1196-1225[Crossref], [PubMed], [CAS], Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xms1WqtLo%253D&md5=4414aa269abf048c4b7ce3bcefd49107Increased mu opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine cravingZubieta, Jon-Kar; Gorelick, David A.; Stauffer, Robin; Ravert, Hayden T.; Dannals, Robert F.; Frost, J. JamesNature Medicine (New York) (1996), 2 (11), 1225-1229CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Co.)The endogenous opioid system has been recently implicated in the reinforcing actions of cocaine and other addictive drugs. In this study we examd. μ opioid receptor binding in ten cocaine-dependent men and seven nonaddicted controls using positron emission tomog. and [11C]carfentanil. Mu opioid binding was increased in several brain regions of the cocaine addicts studied 1-4 days after their last use of cocaine. Binding was pos. correlated with the severity of cocaine craving experienced at the time. The upregulation of μ opioid receptor binding persisted after 4 wk of monitored cocaine abstinence. These findings demonstrate for the first time the involvement of the endogenous opioid system in cocaine dependence and cocaine craving in living human subjects.353Gorelick, D. A.; Kim, Y. K.; Bencherif, B.; Boyd, S. J.; Nelson, R.; Copersino, M.; Endres, C. J.; Dannals, R. F.; Frost, J. J. Imaging brain mu-opioid receptors in abstinent cocaine users: Time course and relation to cocaine craving. Biol. Psychiatry 2005, 57, 1573– 1582, DOI: 10.1016/j.biopsych.2005.02.026[Crossref], [PubMed], [CAS], Google Scholar353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlt1Grsb8%253D&md5=3c0ca2be00051adc4bd89bcc2502183eImaging brain Mu-opioid receptors in abstinent cocaine users: time course and relation to cocaine cravingGorelick, David A.; Kim, Yu Kyeong; Bencherif, Badreddine; Boyd, Susan J.; Nelson, Richard; Copersino, Marc; Endres, Christopher J.; Dannals, Robert F.; Frost, J. JamesBiological Psychiatry (2005), 57 (12), 1573-1582CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)Background: Cocaine treatment upregulates brain mu-opioid receptors (mOR) in animals. Human data regarding this phenomenon are limited. We previously used positron emission tomog. (PET) with [11C]-carfentanil to show increased mOR binding in brain regions of 10 cocaine-dependent men after 1 and 28 days of abstinence. Methods: Regional brain mOR binding potential (BP) was measured with [11C]carfentanil PET scanning in 17 cocaine users over 12 wk of abstinence on a research ward and in 16 healthy control subjects. Results: Mu-opioid receptor BP was increased in the frontal, anterior cingulate, and lateral temporal cortex after 1 day of abstinence. Mu-opioid receptor BP remained elevated in the first two regions after 1 wk and in the anterior cingulate and anterior frontal cortex after 12 wk. Increased binding in some regions at 1 day and 1 wk was pos. correlated with self-reported cocaine craving. Mu-opioid receptor BP was significantly correlated with percentage of days with cocaine use and amt. of cocaine used per day of use during the 2 wk before admission and with urine benzoylecgonine concn. at the first PET scan. Conclusions: These results suggest that chronic cocaine use influences endogenous opioid systems in the human brain and might explain mechanisms of cocaine craving and reinforcement.354Weerts, E. M.; Wand, G. S.; Kuwabara, H.; Munro, C. A.; Dannals, R. F.; Hilton, J.; Frost, J. J.; McCaul, M. E. Positron emission tomography imaging of mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjects: PET imaging of opioid receptors in alcoholics. Alcohol.: Clin. Exp. Res. 2011, 35, 2162– 2173, DOI: 10.1111/j.1530-0277.2011.01565.x[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVCqsL4%253D&md5=2905b03db0df3d05ab7d51304f37bca7Positron emission tomography imaging of Mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjectsWeerts, Elise M.; Wand, Gary S.; Kuwabara, Hiroto; Munro, Cynthia A.; Dannals, Robert F.; Hilton, John; Frost, J. James; McCaul, Mary E.Alcoholism: Clinical & Experimental Research (2011), 35 (12), 2162-2173CODEN: ACRSDM; ISSN:0145-6008. (Wiley-Blackwell)Background: The endogenous opioid system plays a significant role in alc. dependence. The goal of the current study was to investigate regional brain mu-opioid receptor (MOR) and delta-opioid receptor (DOR) availability in recently abstinent alc.-dependent and age-matched healthy control men and women with positron emission tomog. (PET) imaging. Methods: Alc.-dependent subjects completed an inpatient protocol, which included medically supervised withdrawal and PET imaging on day 5 of abstinence. Control subjects completed PET imaging following an overnight stay. PET scans with the MOR-selective ligand [11C]carfentanil (CFN) were completed in 25 alc.-dependent and 30 control subjects. Most of these same subjects (20 alc.-dependent subjects and 18 controls) also completed PET scans with the DOR-selective ligand [11C]methylnaltrindole (MeNTL). Results: Vols. of interest and statistical parametric mapping analyses indicated that alc.-dependent subjects had significantly higher [11C]CFN binding potential (BPND) than healthy controls in multiple brain regions including the ventral striatum when adjusting for age, gender, and smoking status. There was an inverse relationship between [11C]CFN BPND and craving in several brain regions in alc.-dependent subjects. Groups did not differ in [11C]MeNTL BPND; however, [11C]MeNTL BPND in caudate was pos. correlated with recent alc. drinking in alc.-dependent subjects. Conclusions: Our observation of higher [11C]CFN BPND in alc.-dependent subjects can result from up-regulation of MOR and/or redn. in endogenous opioid peptides following long-term alc. consumption, dependence, and/or withdrawal. Alternatively, the higher [11C]CFN BPND in alc.-dependent subjects may be an etiol. difference that predisposed these individuals to alc. dependence or may have developed as a result of increased exposure to childhood adversity, stress, and other environmental factors known to increase MOR. Although the direction of group differences in [11C]MeNTL BPND was similar in many brain regions, differences did not achieve statistical significance, perhaps as a result of our limited sample size. Addnl. research is needed to further clarify these relationships. The finding that alc.-dependent subjects had higher [11C]CFN BPND is consistent with a prominent role of the MOR in alc. dependence.355Banati, R. B.; Newcombe, J.; Gunn, R. N.; Cagnin, A.; Turkheimer, F.; Heppner, F.; Price, G.; Wegner, F.; Giovannoni, G.; Miller, D. H.; Perkin, G. D.; Smith, T.; Hewson, A. K.; Bydder, G.; Kreutzberg, G. W.; Jones, T.; Cuzner, M. L.; Myers, R. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000, 123, 2321– 2337, DOI: 10.1093/brain/123.11.2321[Crossref], [PubMed], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M%252FktFertQ%253D%253D&md5=7afeb2a31af663605d53c0a1a65e6d1fThe peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activityBanati R B; Newcombe J; Gunn R N; Cagnin A; Turkheimer F; Heppner F; Price G; Wegner F; Giovannoni G; Miller D H; Perkin G D; Smith T; Hewson A K; Bydder G; Kreutzberg G W; Jones T; Cuzner M L; Myers RBrain : a journal of neurology (2000), 123 ( Pt 11) (), 2321-37 ISSN:0006-8950.This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.356Lloyd, C. M.; Richardson, M. P.; Brooks, D. J.; Al-Chalabi, A.; Leigh, P. N. Extramotor involvement in ALS: PET studies with the GABAA ligand [11C]flumazenil. Brain 2000, 123, 2289– 2296, DOI: 10.1093/brain/123.11.2289[Crossref], [PubMed], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M%252FktFersQ%253D%253D&md5=7f5a9b6baa8dd9a2f5f9df3bca8b5b4eExtramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenilLloyd C M; Richardson M P; Brooks D J; Al-Chalabi A; Leigh P NBrain : a journal of neurology (2000), 123 ( Pt 11) (), 2289-96 ISSN:0006-8950.We used the benzodiazepine GABA(A) marker [(11)C] flumazenil to study cerebral dysfunction in amyotrophic lateral sclerosis (ALS) with PET. Seventeen non-demented patients with clinically definite or probable ALS were scanned and statistical parametric maps were derived to localize changes in regional flumazenil volumes of distribution (FMZVD), which correlate closely with receptor density (B(max)), and the results were compared with those of 17 controls. The ALS group showed statistically significant decreases in relative FMZVD in the prefrontal cortex (areas 9 and 10 bilaterally), parietal cortex (area 7 bilaterally), visual association cortex (area 18 bilaterally) and left motor/premotor cortex (including area 4) (P < 0.001). Relative reductions in FMZVD were also seen in the left ventrolateral and dorsolateral prefrontal cortex (areas 45, 46 and 47), Broca's area and the right temporal (area 21) and right visual association cortex (area 19). These observations suggest that cerebral dysfunction in ALS involves motor/premotor and extramotor areas, particularly the prefrontal regions.357Künig, G.; Leenders, K. L.; Sanchez-Pernaute, R.; Antonini, A.; Vontobel, P.; Verhagen, A.; Günther, I. Benzodiazepine receptor binding in Huntington’s disease: [11C]flumazenil uptake measured using positron emission tomography. Ann. Neurol. 2000, 47, 644– 648, DOI: 10.1002/1531-8249(200005)47:5<644::AID-ANA13>3.0.CO;2-C358Lingford-Hughes, A. R.; Wilson, S. J.; Cunningham, V. J.; Feeney, A.; Stevenson, B.; Brooks, D. J.; Nutt, D. J. GABA-benzodiazepine receptor function in alcohol dependence: A combined 11C-flumazenil PET and pharmacodynamic study. Psychopharmacology (Berl). 2005, 180, 595– 606, DOI: 10.1007/s00213-005-2271-x[Crossref], [PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVSqt7vN&md5=da8b7335e00f7cc7fb5239a686c48da1GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic studyLingford-Hughes, A. R.; Wilson, S. J.; Cunningham, V. J.; Feeney, A.; Stevenson, B.; Brooks, D. J.; Nutt, D. J.Psychopharmacology (Berlin, Germany) (2005), 180 (4), 595-606CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alc. dependence. We used positron emission tomog. (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to det. in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Abstinent male alc. dependent subjects underwent [11C]flumazenil PET to measure occupancy of BDZ receptors by midazolam while recording its pharmacodynamic effects on behavioral and physiol. measures. Rate consts. describing the exchange of [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. A 50% redn. in electroencephalog. (EEG)-measured sleep time was seen in the alc. dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG beta1 power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metab. were found between the groups. In summary, our study suggests that alc. dependence in man is assocd. with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alc. dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.359Myers, J. F.; Comley, R. A.; Gunn, R. N. Quantification of [11C]Ro15–4513 GABAAα5 specific binding and regional selectivity in humans. J. Cereb. Blood Flow Metab. 2017, 37, 2137– 2148, DOI: 10.1177/0271678X16661339[Crossref], [PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFKms74%253D&md5=a1a64d8e83b197a002bbf2f294244034Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humansMyers, Jim FM; Comley, Robert A.; Gunn, Roger N.Journal of Cerebral Blood Flow & Metabolism (2017), 37 (6), 2137-2148CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)[11C]Ro15-4513 has been introduced as a positron emission tomog. radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different anal. approaches has yet to be performed. Using human heterologous competition data, with [11C]Ro15-4513 and the highly selective GABAAα5 selective neg. allosteric modulator Basmisanil (RG1662), we quantify the GABAAα5 selectivity of [11C]Ro15-4513, assess the validity of ref. tissues and evaluate the performance of four different kinetic anal. methods. The results show that [11C]Ro15-4513 has high but not complete selectivity for GABAAα5, with α5 representing around 60-70% of the specific binding in α5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of α5 signal and might be used as ref. regions under certain conditions. Off-target non-selective binding to other GABAA subtypes means that the choice of anal. method and the interpretation of outcome measures must be considered carefully. We discuss the merits of two tissue compartmental model analyses to derive both VT and VS, band-pass spectral anal. for estn. of Vα5 and the simplified ref. tissue model for estn. of BPND.360Diksic, M.; Tohyama, Y.; Takada, A. Brain net unidirectional uptake of alpha-[14C]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp. Neurochem. Res. 2000, 25, 1537– 1546, DOI: 10.1023/A:1026654116999[Crossref], [PubMed], [CAS], Google Scholar360https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovFyhtrs%253D&md5=f170a9fc6e5df59e7b7e78a06f4165b4Brain net unidirectional uptake of α-[14C]methyl-L-tryptophan (α-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and α-MTrpDiksic, Mirko; Tohyama, Yoshihiro; Takada, AkiraNeurochemical Research (2000), 25 (12), 1537-1546CODEN: NEREDZ; ISSN:0364-3190. (Kluwer Academic/Plenum Publishers)The uptake and trapping consts. for labeled tryptophan (Trp) via the serotonin (5-hydroxytryptamine; 5-HT) metabolic pathway and for the incorporation of Trp into proteins, and α-[14C]methyl-L-tryptophan (α-MTrp) were measured. Measurements were done in rats treated with either saline or probenecid (200 mg/kg). In addn., the blood-brain barrier (BBB) permeability surface area products for Trp (PST) and α-MTrp (PSα) were measured in normal rats. The results suggest that, in both groups of rats, there is a highly significant correlation (Pearson Product Moment Correlation (PPMC)) between the brain uptake and trapping consts. for α-MTrp and those of Trp via the 5-HT metabolic pathway, but there is no significant correlation (PPMC) between either of these consts. and the PS products of either compd. There is also no significant correlation (PPMC) between the const. for the Trp incorporation into proteins with any of the other parameters. For all parameters, except Trp incorporation into proteins (α-MTrp is not incorporated into proteins), there was a highly significant correlation between the quantities measured for Trp and α-MTrp. The data presented here strongly suggests that the brain uptake and trapping of α-MTrp relates to brain 5-HT synthesis, and does not relate to the BBB transport or protein incorporation of Trp. On the basis of these results, as well as those previously reported, the authors concluded that trapping (unidirectional uptake) of α-MTrp can be converted to the 5-HT synthesis rates in the brain. From this also follows that labeled α-MTrp is a good tracer for in vivo evaluation of the brain 5-HT synthesis.361Chugani, H. T.; Juhász, C.; Chugani, D. C.; Lawrenson, L.; Muzik, O.; Chakraborty, P. K.; Sood, S. Increased striatal serotonin synthesis following cortical resection in children with intractable epilepsy. Epilepsy Res. 2008, 78, 124– 130, DOI: 10.1016/j.eplepsyres.2007.10.012[Crossref], [PubMed], [CAS], Google Scholar361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVOrsL8%253D&md5=11536dce2403efb889af4f3ffd21f939Increased striatal serotonin synthesis following cortical resection in children with intractable epilepsyChugani, Harry T.; Juhasz, Csaba; Chugani, Diane C.; Lawrenson, Lesley; Muzik, Otto; Chakraborty, Pulak K.; Sood, SandeepEpilepsy Research (2008), 78 (2-3), 124-130CODEN: EPIRE8; ISSN:0920-1211. (Elsevier Ltd.)Summary: Background and purpose: Serotonin is a major regulator of structural brain plasticity, which may occur following cortical resection in humans. In this study we used positron emission tomog. (PET) with alpha[11C]methyl--tryptophan (AMT) to evaluate serotonergic alterations in subcortical structures following cortical resection in children with intractable epilepsy. Methods: AMT uptake in the thalamus and lentiform nucleus was evaluated postoperatively (1-89 mo following resection) in 19 children (mean age: 8.7 years) with a previous cortical resection due to intractable epilepsy. Ten children with partial epilepsy but without resection and seven normal children served as controls. Results: There was an increased AMT uptake in the lentiform nucleus ipsilateral to the resection as compared to the contralateral side (mean asymmetry: 4.2 ± 3.0%), and the asymmetries were significantly higher than those measured in the control groups (p ≤ 0.001). Post-resection asymmetry indexes in the lentiform nucleus correlated inversely with postoperative time (r = -0.67; p = 0.002), but not with age (p = 0.29) or the extent of resection (p = 0.77). In contrast, thalamic AMT uptake asymmetries were not different among the three groups (p = 0.63). Conclusions: Cortical resection results in a sustained increase of AMT uptake in the lentiform nucleus, suggesting increased serotonin synthesis. Serotonergic activation in the deafferented striatum may play a role in the functional reorganization of cortico-striatal projections in humans.362Barnes, N. M.; Sharp, T. A review of central 5-HT receptors and their function. Neuropharmacology 1999, 38, 1083– 1152, DOI: 10.1016/S0028-3908(99)00010-6[Crossref], [PubMed], [CAS], Google Scholar362https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXltVCgsrg%253D&md5=7e92e3b6586ce16c00a1afab5ae06e01A review of central 5-HT receptors and their functionBarnes, Nicholas M.; Sharp, TrevorNeuropharmacology (1999), 38 (8), 1083-1152CODEN: NEPHBW; ISSN:0028-3908. (Elsevier Science Ltd.)A review with ∼700 refs. It is now nearly 5 yr since the last of the currently recognized 5-HT receptors was identified in terms of its cDNA sequence. Over this period, much effort has been directed towards understanding the function attributable to individual 5-HT receptors in the brain. This has been helped, in part, by the synthesis of a no. of compds. that selectively interact with individual 5-HT receptor subtypes-although some 5-HT receptors still lack any selective ligands (e.g., 5-ht1E, 5-ht5A and 5-ht5B receptors). The present review provides background information for each 5-HT receptor subtype and subsequently reviews in more detail the functional responses attributed to each receptor in the brain. Clearly this latter area has moved forward in recent years and this progression is likely to continue given the level of interest assocd. with the actions of 5-HT. This interest is stimulated by the belief that pharmacol. manipulation of the central 5-HT system will have therapeutic potential. In support of which, a no. of 5-HT receptor ligands are currently utilized, or are in clin. development, to reduce the symptoms of CNS dysfunction.363Herholz, K.; Heiss, W. Positron emission tomography in clinical neurology. Molecular Imaging & Biology. 2004, 6, 239– 269, DOI: 10.1016/j.mibio.2004.05.002[Crossref], [PubMed], [CAS], Google Scholar363https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2czmtVGisQ%253D%253D&md5=5d401521383f20decb95714a6b94437ePositron emission tomography in clinical neurologyHerholz Karl; Heiss W-DMolecular imaging and biology (2004), 6 (4), 239-69 ISSN:1536-1632.Positron emission tomography (PET) imaging in clinical neurology serves several purposes: differential diagnosis, especially in the early stage of neurologic disorders, description of pathophysiologic changes that are responsible for manifestation and course of a disease, and evaluation and follow-up of treatment effects. Many of these applications are possible with the most widely available PET tracer, 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Additional tracers are used clinically to detect the disturbance of specific neurotransmitter and receptor systems, blood flow, oxygen metabolism, and amino acid uptake. Main diagnostic issues addressed in this review are early diagnosis of Alzheimer's disease and other dementias, differential diagnosis of movement disorders, diagnosis of recurrent brain tumors, identification of viable tissue in ischemic stroke, and localization of epileptogenic foci. Techniques for presurgical localization of eloquent cortex and monitoring of therapy are presented.364Azmitia, E.; Gannon, P.; Kheck, N.; Whitakerazinitia, P. Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology 1996, 14, 35– 46, DOI: 10.1016/S0893-133X(96)80057-1[Crossref], [PubMed], [CAS], Google Scholar364https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XpvVeqtA%253D%253D&md5=f9c0a5b470a9b8a589a4c243e11cb2a7Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cellsAzmitia, Efrain C.; Gannon, Patrick J.; Kheck, Nancy M.; Whitaker-Azmitia, Patricia M.Neuropsychopharmacology (1996), 14 (1), 35-46CODEN: NEROEW; ISSN:0893-133X. (Elsevier)Activation of 5HT1A receptors produces many different physiol. responses, which may be due to their localization on diverse cells in the brain. A 5-HT1A receptor antipeptide (aa170-186) antibody was produced that showed both high titer for peptide binding and immunocytochem. staining. Studies performed in perfusion-fixed brain tissue showed immunoreactive neurons, glial, and ependymal cells in the rat, mouse, cat, and monkey. Results from the studies of Macaca fascicularis brains are presented. The authors obsd. two main neuronal labeling patterns in the primate brain: (1) A general, diffuse somatodendritic distribution of 5-HT1A receptor immunoreactivity is seen in the raphe nuclei where the dendritic shaft, its branches and spines, and the entire perikaryon are immunolabeled. This pattern is also obsd. in the nucleus locus ceruleus, in scattered large brainstem reticular neurons, and in dentate gyrus hilar interneurons. (2) A discrete localization of 5-HT1A receptor immunoreactivity on the initial axon segment (axon hillock) is noted in pyramidal neurons of layer III and V of cerebral cortex, Cornu Ammonus (1-4) of the hippocampus, and in most brainstem and cervical spinal cord motoneurons. In addn. to neuronal labeling, 5-HT1A receptor immunoreactivity is seen in the cell body and processes of astrocytes, and other nonneuronal cells. This pattern is particularly evident in the white matter of cerebral cortex and spinal cord, the pontine nuclei, the brainstem tectum, and the hilus of the dentate gyrus. The clin. implications of 5-HT1A cellular localization are briefly discussed.365Turner, M. R. [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. Brain 2005, 128, 896– 905, DOI: 10.1093/brain/awh428[Crossref], [PubMed], [CAS], Google Scholar365https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M7lsV2jsg%253D%253D&md5=7ed9b261f178a93c945a21cd82b8051611C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALSTurner M R; Rabiner E A; Hammers A; Al-Chalabi A; Grasby P M; Shaw C E; Brooks D J; Leigh P NBrain : a journal of neurology (2005), 128 (Pt 4), 896-905 ISSN:.The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.366Lanctôt, K. L.; Herrmann, N.; Ganjavi, H.; Black, S. E.; Rusjan, P. M.; Houle, S.; Wilson, A. A. Serotonin-1A receptors in frontotemporal dementia compared with controls. Psychiatry Res., Neuroimaging 2007, 156, 247– 250, DOI: 10.1016/j.pscychresns.2007.07.003[Crossref], [CAS], Google Scholar366https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlGgs7bJ&md5=3bc8bc1ce2c26de6fcbb0c471e5da82cSerotonin-1A receptors in frontotemporal dementia compared with controlsLanctot, Krista L.; Herrmann, Nathan; Ganjavi, Hooman; Black, Sandra E.; Rusjan, Pablo M.; Houle, Sylvain; Wilson, Alan A.Psychiatry Research, Neuroimaging (2007), 156 (3), 247-250CODEN: PSREEK; ISSN:0925-4927. (Elsevier Ltd.)Using PET neuroimaging, we demonstrated that four frontotemporal lobar dementia (FTLD) patients had significantly decreased serotonin 5-HT1A binding potential (BP) compared with controls in all 10 brain regions examd. These pilot data suggest that profound 5-HT1A BP losses may be present and contribute to symptomatol. and treatment response in FTLD.367Goffin, K.; Dedeurwaerdere, S.; Van Laere, K.; Van Paesschen, W. Neuronuclear assessment of patients with epilepsy. Semin. Nucl. Med. 2008, 38, 227– 239, DOI: 10.1053/j.semnuclmed.2008.02.004[Crossref], [PubMed], [CAS], Google Scholar367https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1czltVyntg%253D%253D&md5=f16ac2f3febec0a6dca57282df1475e8Neuronuclear assessment of patients with epilepsyGoffin Karolien; Dedeurwaerdere Stefanie; Van Laere Koen; Van Paesschen WimSeminars in nuclear medicine (2008), 38 (4), 227-39 ISSN:0001-2998.Epilepsy is a common chronic neurological disorder that is controlled with medication in approximately 70% of cases. When partial seizures are recurrent despite the use of antiepileptic drugs, resection of the epileptogenic cortex may be considered. Nuclear medicine plays an important role in the presurgical assessment of patients with refractory epilepsy. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques are used to determine the seizure onset zone, which needs to be resected to render a patient seizure free. Correct localization of the ictal onset zone with the use of SPECT or PET is associated with a better surgical outcome. Ictal perfusion SPECT imaging with (99m)Tc-ethyl cysteinate dimer (ECD) or (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) enables one to detect the seizure onset zone in a majority of cases, especially in patients with temporal lobe epilepsy. Interictal SPECT imaging, which is more widely available, is unreliable to determine the ictal onset zone and is usually only used for comparison with ictal SPECT images. Assessment of the ictal onset zone using subtracted ictal and interictal studies, overlayed on structural imaging has proven to be more sensitive and more specific compared with visual assessment. Video-electroencephalography monitoring in combination with ictal SPECT imaging, however, is only available in specialized centers. It is important to inject the perfusion tracer as early as possible after the beginning of a seizure and to be aware of patterns of seizure propagation. Interictal (18)F-fluorodeoxyglucose (FDG)-PET is routinely used to detect brain areas of hypometabolism, which usually encompass, but tend to be larger than, the seizure onset zone. Also, for assessment of FDG-PET, it is advisable to use an automated technique comparing the patient's images to a normal database in addition to visual interpretation of the images, since automated techniques have proven to be more accurate. In view of the thickness of the cortical ribbon, which may be below the resolution of the PET camera, posthoc partial volume correction or PET reconstruction incorporating the anatomical information of magnetic resonance imaging (MRI), may be useful for optimal assessment of glucose metabolism. Perfusion SPECT and interictal FDG-PET are able to demonstrate areas of abnormal perfusion and metabolism at a distance from the ictal onset zone, which may be associated with cognitive and psychiatric comorbidities, and may represent the functional deficit zone in epilepsy. Part of the functional deficit zone is a dynamic seizure-related process, which may resolve with cessation of seizures. In recent years, novel PET tracers have been developed to visualize not only glucose metabolism but also a wide variety of specific receptor systems. In patients with epilepsy, changes in the gamma-amino-butyric acid(A) receptor, opioid receptor, 5-HT(1A) serotonin receptor, nicotinic acetylcholine receptor systems, and others have been described. Because these tracers are not widely available and the superiority of studying these receptor systems over glucose metabolism in the presurgical evaluation of patients with refractory epilepsy remains to be proven, their use in clinical practice is limited at the moment. Finally, advances in small animal PET scanning allow the in vivo study of the process of epileptogenesis, starting from an initial brain insult to the development of seizures, in animal models of epilepsy. Potential new therapeutic targets may be discovered using this translational approach.368Passchier, J.; van Waarde, A. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. Eur. J. Nucl. Med. 2001, 28, 113– 129, DOI: 10.1007/s002590000394[Crossref], [PubMed], [CAS], Google Scholar368https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovFyjt7g%253D&md5=3964aa4056633399d6ac2843fafaceb1Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous systemPasschier, Jan; van Waarde, ArenEuropean Journal of Nuclear Medicine (2001), 28 (1), 113-129CODEN: EJNMD9; ISSN:0340-6997. (Springer-Verlag)A review with 131 refs. The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behavior, motion sickness and eating disorders, they are an important target for drug therapy. Here, the authors review the radioligands which are available for visualization and quantification of this important neuroreceptor in the human brain, using positron emission tomog. (PET) or single-photon emission tomog. (SPET). More than 20 compds. have been labeled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogs of the agonist, 8-OH-DPAT, structural analogs of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-11C] WAY-100635 (WAY), [carbonyl-11C]desmethyl-WAY-100635 (DWAY),p-[18F]MPPF and [11C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT1A receptor distribution in the brain (even the raphe nuclei are visualized), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centers within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) prodn. of a radioiodinated or technetium-labeled ligand for SPET.369Pike, V. W. Radioligands for PET studies of central 5-HT receptors and re-uptake sites — Current status. Nucl. Med. Biol. 1995, 22, 1011– 1018, DOI: 10.1016/0969-8051(95)02024-1[Crossref], [PubMed], [CAS], Google Scholar369https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XlvFCjtQ%253D%253D&md5=0a8aa8601f9b597465cec1997a0aefb8Radioligands for PET studies of central 5-HT receptors and re-uptake sites - current statusPike, Victor W.Nuclear Medicine and Biology (1995), 22 (8, New Radio-Tracers and Methods of Quality Assurance for Nuclear Medicine Applications), 1011-18CODEN: NMBIEO; ISSN:0883-2897. (Elsevier)A review and discussion, with several refs.370Innis, R. B.; Cunningham, V. J.; Delforge, J.; Fujita, M.; Gjedde, A.; Gunn, R. N.; Holden, J.; Houle, S.; Huang, S.-C.; Ichise, M.; Iida, H.; Ito, H.; Kimura, Y.; Koeppe, R. A.; Knudsen, G. M.; Knuuti, J.; Lammertsma, A. A.; Laruelle, M.; Logan, J.; Maguire, R. P.; Mintun, M. A.; Morris, E. D.; Parsey, R.; Price, J. C.; Slifstein, M.; Sossi, V.; Suhara, T.; Votaw, J. R.; Wong, D. F.; Carson, R. E. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J. Cereb. Blood Flow Metab. 2007, 27, 1533– 1539, DOI: 10.1038/sj.jcbfm.9600493[Crossref], [PubMed], [CAS], Google Scholar370https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXptlSqtrc%253D&md5=77f7e875203e18e1a15d3e2d7fcd4ac6Consensus nomenclature for in vivo imaging of reversibly binding radioligandsInnis, Robert B.; Cunningham, Vincent J.; Delforge, Jacques; Fujita, Masahiro; Gjedde, Albert; Gunn, Roger N.; Holden, James; Houle, Sylvain; Huang, Sung-Cheng; Ichise, Masanori; Iida, Hidehiro; Ito, Hiroshi; Kimura, Yuichi; Koeppe, Robert A.; Knudsen, Gitte M.; Knuuti, Juhani; Lammertsma, Adriaan A.; Laruelle, Marc; Logan, Jean; Maguire, Ralph Paul; Mintun, Mark A.; Morris, Evan D.; Parsey, Ramin; Price, Julie C.; Slifstein, Mark; Sossi, Vesna; Suhara, Tetsuya; Votaw, John R.; Wong, Dean F.; Carson, Richard E.Journal of Cerebral Blood Flow & Metabolism (2007), 27 (9), 1533-1539CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)A review. An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo mol. imaging of reversibly binding radioligands.371Bhagwagar, Z.; Hinz, R.; Taylor, M.; Fancy, S.; Cowen, P.; Grasby, P. Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: A positron emission study with [(11)C]MDL 100,907. Am. J. Psychiatry 2006, 163, 1580– 1587, DOI: 10.1176/ajp.2006.163.9.1580[Crossref], [PubMed], [CAS], Google Scholar371https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28ritFGmtg%253D%253D&md5=5dd5c3caf0260a447a8b0e97b9f656c7Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907Bhagwagar Zubin; Hinz Rainer; Taylor Matthew; Fancy Sabrina; Cowen Philip; Grasby PaulThe American journal of psychiatry (2006), 163 (9), 1580-7 ISSN:0002-953X.OBJECTIVE: A previous positron emission tomography (PET) study reported increased serotonin 5-HT(2A) receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT(2A) receptor ligand [(11)C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT(2A) receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. METHOD: Cortical 5-HT(2A) receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [(11)C]MDL 100,907 in brain tissue. RESULTS: Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT(2A) receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT(2A) receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients. CONCLUSIONS: These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT(2A) receptors. The correlation of increased 5-HT(2A) receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT(2A) receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.372Azmitia, E. C.; Nixon, R. Dystrophic serotonergic axons in neurodegenerative diseases. Brain Res. 2008, 1217, 185– 194, DOI: 10.1016/j.brainres.2008.03.060[Crossref], [PubMed], [CAS], Google Scholar372https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsFCqsLg%253D&md5=73028faf2e2dcb972b9fa7973a4321adDystrophic serotonergic axons in neurodegenerative diseasesAzmitia, Efrain C.; Nixon, RalphBrain Research (2008), 1217 (), 185-194CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)Neurodegenerative diseases such as Parkinson's disease (PD), frontal lobe dementia (FLD) and diffuse Lewy-body dementia (DLBD) have diverse neuropathol. features. Here we report that serotonin fibers are dystrophic in the brains of individuals with these three diseases. In neuropathol. normal (control) brains (n = 3), serotonin axons immunoreactive (IR) with antibodies against the serotonin transporter (5-HTT) protein were widely distributed in cortex (entorhinal and dorsolateral prefrontal), hippocampus and rostral brainstem. 5-HTT-IR fibers-of-passage appeared thick, smooth, and unbranched in medial forebrain bundle, medial lemniscus and cortex white matter. The terminal branches were fine, highly branched and varicose in substantia nigra, hippocampus and cortical gray matter. In the diseased brains, however, 5-HTT-IR fibers in the forebrain were reduced in no. and were frequently bulbous, splayed, tightly clustered and enlarged. Morphometric anal. revealed significant differences in the size distribution of the 5-HTT-IR profiles in dorsolateral prefrontal area between neurodegenerative diseases and controls. Our observations provide direct morphol. evidence for degeneration of human serotonergic axons in the brains of patients with neurodegenerative diseases despite the limited size (n = 3 slices for each region (3) from each brain (4), total slices was n = 36) and the lack of extensive clin. characterization of the analyzed cohort. This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue.373Buck, A.; Gucker, P. M.; Schönbächler, R. D.; Arigoni, M.; Kneifel, S.; Vollenweider, X. F.; Ametamey, S. M.; Burger, C. Evaluation of serotonergic transporters using PET and [11C](+)McN-5652: Assessment of methods. J. Cereb. Blood Flow Metab. 2000, 20, 253– 262, DOI: 10.1097/00004647-200002000-00005[Crossref], [PubMed], [CAS], Google Scholar373https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhs1alur4%253D&md5=4e5a169f39551e093fec756b2117196cEvaluation of serotonergic transporters using PET and [11C](+)McN-5652: assessment of methodsBuck, Alfred; Gucker, Pascale M.; Schonbachler, Roland D.; Arigoni, Michele; Kneifel, Stefan; Vollenweider, Franz X.; Ametamey, Simon M.; Burger, CyrillJournal of Cerebral Blood Flow and Metabolism (2000), 20 (2), 253-262CODEN: JCBMDN; ISSN:0271-678X. (Lippincott Williams & Wilkins)[11C](+)McN-5652 is an established positron emission tomog. tracer used to assess serotonergic transporter d. Several methods have been used to analyze [11C](+)McN-5652 data; however, no evaluation of candidate methods has been published in detail yet. In this study, compartmental modeling using a one-tissue compartment model (K1, k2"), a two-tissue compartment model (K1 to k4), and a noncompartmental method that relies on a ref. region devoid of specific binding sites were assessed. Because of its low d. of serotonergic transporters, white matter was chosen as ref. Parameters related to transporter d. were the total distribution vol. DV" (= K1/k2", one tissue compartment), DVtot (= K1/k1' (1 + k3/k4), two tissue compartments), and Rv (= k3'/k4, noncompartmental method). The DV", DVtot, and Rv values extended over a similar range and reflected the known pattern of serotonergic transporters. However, all parameters related to transporter d. were markedly confounded by nonspecific binding. With regard to K1, the one-tissue compartment model yielded markedly lower values, which were, however, more stable. The minimal study duration needed to det. stable values for the distribution vol. was ∼60 min. The choice of the method to analyze [11C](+)McN-5652 data depends on the situation. Parametric maps of Rv are useful if no information on K1 is needed. If compartmental modeling is chosen, both the one- and the two-tissue compartment models have advantages. The one-tissue compartment model underestimates K1 but yields more robust values. The distribution vols. calcd. with both models contain a similar amt. of information. None of the parameters reflected serotonergic transporter d. in a true quant. manner, as all were confounded by nonspecific binding.374Ginovart, N.; Wilson, A. A.; Meyer, J. H.; Hussey, D.; Houle, S. [11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in cats. Synapse 2003, 47, 123– 133, DOI: 10.1002/syn.10155[Crossref], [PubMed], [CAS], Google Scholar374https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlt1Chsg%253D%253D&md5=70f97154518c6478158709eccfb70fcf[11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in catsGinovart, Nathalie; Wilson, Alan A.; Meyer, Jeffrey H.; Hussey, Doug; Houle, SylvainSynapse (New York, NY, United States) (2003), 47 (2), 123-133CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)The in vivo pharmacol. profile of [11C]-DASB, a new radioligand developed for in vivo imaging of the serotonin transporter (SERT), was evaluated in the cat brain using positron emission tomog. (PET). The in vivo distribution of [11C]-DASB binding was consistent with the known distribution of SERT sites in the cat brain in vitro with high uptakes of radioactivity in the midbrain and thalamus, intermediate levels in striatum, and modest to low levels of radioactivity in the neocortex and cerebellum, resp. [11C]-DASB binding potential (BP) values ranged from about 0.2 in the neocortex to 2.2 in the midbrain. Radioligand binding in all brain regions except cerebellum was markedly reduced following pretreatment with fluoxetine and citalopram, but was unaffected by pretreatment with GBR12909, maprotiline, and haloperidol, indicating specificity of [11C]-DASB binding to the SERT. Two cats were each examd. using PET and [11C]-DASB in a longitudinal fashion (from 30 min and up to 24 days) following a single i.v. dose of: 1. fluoxetine, and 2. citalopram at different dosages. Both drugs induced similar degrees of SERT occupancy at 30 min postinjection (∼90%). A comparison of citalopram and fluoxetine pharmacokinetics in the same animal and at the same dosage (1 mg/kg) showed that citalopram SERT occupancy and plasma half-lives were 9 times and 14 times shorter, resp., than those of fluoxetine and norfluoxetine. In addn., studies performed after injection of the monoamine oxidase inhibitor tranylcypromine suggested that high levels of synaptic serotonin may compete with [11C]-DASB for binding on the SERT. These studies indicate that [11C]-DASB is a suitable PET radioligand for measuring drug occupancy of the SERT in vivo and has potential for monitoring in vivo changes in serotonin levels.375Heiss, W.-D.; Herholz, K. Brain receptor imaging. J. Nucl. Med. 2006, 47, 302– 312[PubMed], [CAS], Google Scholar375https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhslantrk%253D&md5=ddbd0dfb76010abc6f8122f440a59e9aBrain receptor imagingHeiss, Wolf-Dieter; Herholz, KarlJournal of Nuclear Medicine (2006), 47 (2), 302-312CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review. Receptors have a prominent role in brain function, as they are the effector sites of neurotransmission at the postsynaptic membrane, have a regulatory role on presynaptic sites for transmitter reuptake and feedback, and are modulating various functions on the cell membrane. Distribution, d., and activity of receptors in the brain can be visualized by radioligands labeled for SPECT and PET, and the receptor binding can be quantified by appropriate tracer kinetic models, which can be modified and simplified for particular application. Selective radioligands are available for the various transmitter systems, by which the distribution of these receptors in the normal brain and changes in receptor binding during various physiol. activities or resulting from pathol. conditions can be visualized. The quant. imaging for several receptors has gained clin. importance-for example, dopamine (D2) receptors for differential diagnosis of movement disorders and for assessment of receptor occupancy by neuroleptics drugs; serotonin (5-hydroxytryptamine, 5-HT) receptors and the 5-HT transporter in affective disorders and for assessment of activity of antidepressants; nicotinic receptors and acetylcholinesterase as markers of cognitive and memory impairment; central benzodiazepine-binding sites at the γ-aminobutyric acid A (GABAA) receptor complex as markers of neuronal integrity in neurodegenerative disorders, epilepsy, and stroke and as the site of action of benzodiazepines; peripheral benzodiazepine receptors as indicators of inflammatory changes; opioid receptors detecting increased cortical excitability in focal epilepsy but also affected in perception of and emotional response to pain; and several receptor systems affected in drug abuse and craving. Further studies of the various transmitter/receptor systems and their balance and infraction will improve our understanding of complex brain functions and will provide more insight into the pathophysiol. of neurol. and psychiatric disease interaction.376Ouchi, Y.; Yoshikawa, E.; Futatsubashi, M.; Yagi, S.; Ueki, T.; Nakamura, K. Altered brain serotonin transporter and associated glucose metabolism in Alzheimer disease. J. Nucl. Med. 2009, 50, 1260– 1266, DOI: 10.2967/jnumed.109.063008[Crossref], [PubMed], [CAS], Google Scholar376https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrovVSnsg%253D%253D&md5=c71bbd3861c12f6c1e2c829970d8c08fAltered brain serotonin transporter and associated glucose metabolism in Alzheimer diseaseOuchi Yasuomi; Yoshikawa Etsuji; Futatsubashi Masami; Yagi Shunsuke; Ueki Takatoshi; Nakamura KazuhikoJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2009), 50 (8), 1260-6 ISSN:0161-5505.UNLABELLED: Whether preclinical depression is one of the pathophysiologic features of Alzheimer disease (AD) has been under debate. In vivo molecular imaging helps clarify this kind of issue. Here, we examined in vivo changes in the brain serotoninergic system and glucose metabolism by scanning early- to moderate-stage AD patients with and without depression using PET with a radiotracer for the serotonin transporter, (11)C-3-amino-4-(2-dimethylaminomethylphenylsulfanyl) benzonitrile (DASB), and a metabolic marker, (18)F-FDG. METHODS: Fifteen AD patients (8 nondepressed and 7 depressed) and 10 healthy subjects participated. All participants underwent 3-dimensional MRI and quantitative (11)C-DASB PET measurements, followed by (18)F-FDG PET scans in the AD group. Region-of-interest analysis was used to examine changes in (11)C-DASB binding potential estimated quantitatively by the Logan plot method in the serotonergic projection region. In addition, statistical parametric mapping was used to examine whether glucose metabolism in any brain region correlated with levels of (11)C-DASB binding in the dense serotonergic projection region (striatum) in AD. RESULTS: Psychologic evaluation showed that general cognitive function (Mini-Mental State Examination) was similar between the 2 AD subgroups. Striatal (11)C-DASB binding was significantly lower in AD patients, irrespective of depression, than in healthy controls (P < 0.05, corrected), and (11)C-DASB binding in other dense projection areas decreased significantly in the depressive group, compared with the control group. The (11)C-DASB binding potential levels in the subcortical serotonergic projection region correlated negatively with depression score (Spearman correlation, P < 0.01) but not with dementia score. Statistical parametric mapping correlation analysis showed that glucose metabolism in the right dorsolateral prefrontal cortex was positively associated with the level of striatal (11)C-DASB binding in AD. CONCLUSION: The significant reduction in (11)C-DASB binding in nondepressed AD patients suggests that presynaptic serotonergic function is altered before the development of psychiatric problems such as depression in AD. The depressive AD group showed greater and broader reductions in binding, suggesting that a greater loss of serotonergic function relates to more severe psychiatric symptoms in the disease. This serotonergic dysfunction may affect the activity of the right dorsolateral prefrontal cortex, a higher center of cognition and emotion in AD.377Meyer, J. H. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J. Psychiatry Neurosci. 2007, 32, 86– 102[PubMed], [CAS], Google Scholar377https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7ltlGhsg%253D%253D&md5=33a3b6568fcdeedb13d204ee02e4131aImaging the serotonin transporter during major depressive disorder and antidepressant treatmentMeyer Jeffrey HJournal of psychiatry & neuroscience : JPN (2007), 32 (2), 86-102 ISSN:1180-4882.This paper focuses on serotonin transporter 5-HTT imaging to investigate major depressive disorder (MDD) and antidepressant occupancy. Such investigations have only recently been possible as a result of major advances in ligand development. The state of the art method is [11C]DASB PET or [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) positron emission tomography. [11C]DASB is a breakthrough for brain imaging 5-HTT. Compared with previous radioligands, [11C]DASB offers both high selectivity and a favourable ratio of specific binding relative to free and nonspecific binding. These characteristics contribute to valid, reliable quantitation of the 5-HTT binding potential (BP). The 5-HTT BP can be viewed as an index of 5-HTT density in a medication free state, or unblocked 5-HTT density in a medication-treated state. During major depressive episodes with no other axis I comorbidity, either no difference in regional 5-HTT BP or a trend toward elevated 5-HTT BP is typically found. During major depressive episodes (of MDD) with more severe symptoms of pessimism (dysfunctional attitudes), regional 5-HTT BP is elevated. In subjects with major depressive episodes and comorbid axis I psychiatric illnesses, decreased regional 5-HTT BP is often reported. With selective serotonin reuptake inhibitor (SSRI) treatment at doses that distinguish from placebo in the treatment of major depressive episodes, 5-HTT occupancy is approximately 80%, and there is a strong relation between plasma level and occupancy that is not predictable based on affinity alone. Implications of 5-HTT imaging findings for understanding major depressive disorder and antidepressant treatment will be discussed.378Chugani, D. C.; Heyes, M. P.; Kuhn, D. M.; Chugani, H. T. Evidence that α[C-11]methyl-L-tryptophan PET traces tryptophan metabolism via the kynurenine pathway in tuberous sclerosis complex. Soc. Neurosci. Abstr. 1998, 24, 1757, 10010101150379Kumar, A.; Asano, E.; Chugani, H. T. α-[11C]-methyl- L -tryptophan PET for tracer localization of epileptogenic brain regions: Clinical studies. Biomarkers Med. 2011, 5, 577– 584, DOI: 10.2217/bmm.11.68[Crossref], [PubMed], [CAS], Google Scholar379https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlerurvK&md5=c1a5c94ea4ec8a2036aa38a0236c6a89α-[11C]-methyl-L-tryptophan PET for tracer localization of epileptogenic brain regions: clinical studiesKumar, Ajay; Asano, Eishi; Chugani, Harry T.Biomarkers in Medicine (2011), 5 (5), 577-584CODEN: BMIEDG; ISSN:1752-0363. (Future Medicine Ltd.)A review. Of several mol. probes used in PET, only α-[11C]-methyl-L-tryptophan (AMT) is able to pinpoint the epileptic focus itself in the interictal state, by revealing a focus of increased AMT uptake, even when an MRI or glucose metab. PET demonstrates normal findings. AMT PET appears to be particularly useful in patients with tuberous sclerosis complex and in patients with cortical developmental malformations. Although the sensitivity of AMT PET in finding the epileptic focus is about 70%, its specificity is almost 100%, indicating that if AMT PET identifies an area of increased uptake, it likely represents the epileptic focus which needs to be resected for better surgical outcome. In nontuberous sclerosis complex patients with cortical dysplasia, increased AMT uptake is usually assocd. with cortical dysplasia type IIB and a very good surgical outcome. Previously, no imaging modality has been able to predict the exact pathol. subtype or differentiate between epileptogenic and nonepileptogenic lesions interictally. The neuropathol. similarities between tubers and type IIB cortical dysplasia suggest a common mechanism of epilepsy, for which AMT PET is a biomarker. Due to the limited access to AMT PET, as presently it is labeled with 11C, which has a half-life of only 20 min and therefore has to be synthesized on site using a cyclotron, most of the AMT experience has originated primarily from only two centers. Therefore, there is a need for more clin. studies from other centers and this can be greatly facilitated if AMT can be labeled with 18F, a PET radionuclide widely available with a half-life of 110 min.380Kagawa, K.; Chugani, D. C.; Asano, E.; Juhász, C.; Muzik, O.; Shah, A.; Shah, J.; Sood, S.; Kupsky, W. J.; Mangner, T. J.; Chakraborty, P. K.; Chugani, H. T. Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). J. Child Neurol. 2005, 20, 429– 438, DOI: 10.1177/08830738050200050701[Crossref], [PubMed], [CAS], Google Scholar380https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2Mzit1Smug%253D%253D&md5=a4963dd5e72c9098c36dd59e13da388fEpilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET)Kagawa Kenji; Chugani Diane C; Asano Eishi; Juhasz Csaba; Muzik Otto; Shah Aashit; Shah Jagdish; Sood Sandeep; Kupsky William J; Mangner Thomas J; Chakraborty Pulak K; Chugani Harry TJournal of child neurology (2005), 20 (5), 429-38 ISSN:0883-0738.Tuberous sclerosis complex is commonly associated with medically intractable seizures. We previously demonstrated that high uptake of alpha-[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) occurs in a subset of epileptogenic tubers consistent with the location of seizure focus. In the present study, we analyzed the surgical outcome of children with tuberous sclerosis complex in relation to AMT PET results. Seventeen children (mean age 4.7 years) underwent epilepsy surgery, guided by long-term videoelectroencephalography (EEG) (including intracranial EEG in 14 cases), magnetic resonance imaging (MRI), and AMT PET. AMT uptake values of cortical tubers were measured using regions of interest delineated on coregistered MRI and were divided by the value for normal-appearing cortex to obtain an AMT uptake ratio. Based on surgical outcome data, tubers showing increased AMT uptake (uptake ratio greater than 1.00) were classified into three categories: (1) epileptogenic (tubers within an EEG-defined epileptic focus whose resection resulted in seizure-free outcome), (2) nonepileptogenic (tubers that were not resected but the patient became seizure free), or (3) uncertain (all other tubers). Increased AMT uptake was found in 30 tubers of 16 children, and 23 of these tubers (77%) were located in an EEG-defined epileptic focus. The tuber with the highest uptake was located in an ictal EEG onset region in each patient. Increased AMT uptake indicated an epileptic region not suspected by scalp EEG in four cases. Twelve children (71%) achieved seizure-free outcome (median follow-up 15 months). Based on outcome criteria, 19 of 30 tubers (63%) with increased AMT uptake were epileptogenic, and these tubers had significantly higher AMT uptake than the nonepileptogenic ones (P = .009). Tubers with at least 10% increase of AMT uptake (in nine patients) were all epileptogenic. Using a cutoff threshold of 1.02 for AMT uptake ratio provided an optimal accuracy of 83% for detecting tubers that needed to be resected to achieve a seizure-free outcome. The findings suggest that resection of tubers with increased AMT uptake is highly desirable to achieve seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery.381Wakamoto, H.; Chugani, D. C.; Juhász, C.; Muzik, O.; Kupsky, W. J.; Chugani, H. T. Alpha-methyl-l-tryptophan positron emission tomography in epilepsy with cortical developmental malformations. Pediatric Neurology. 2008, 39, 181– 188, DOI: 10.1016/j.pediatrneurol.2008.05.014[Crossref], [PubMed], [CAS], Google Scholar381https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnivFGisw%253D%253D&md5=b1739c28aa40510e70cd143e701dd3d9Alpha-methyl-l-tryptophan positron emission tomography in epilepsy with cortical developmental malformationsWakamoto Hiroyuki; Chugani Diane C; Juhasz Csaba; Muzik Otto; Kupsky William J; Chugani Harry TPediatric neurology (2008), 39 (3), 181-8 ISSN:0887-8994.Preliminary studies suggest that alpha[(11)C]methyl-l-tryptophan positron emission tomography can detect the epileptic focus within malformations of cortical development. We determined the sensitivity and specificity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography in identifying epileptic focus in children with intractable, neocortical epilepsy with and without malformations of cortical development. Seventy-three epileptic children were classified into lesional and nonlesional groups, and compared regarding focal increased alpha-[(11)C]methyl-l-tryptophan uptake. The sensitivity and specificity of focal increased alpha-[(11)C]methyl-l-tryptophan uptake, using intracranial electroencephalogram localization of seizure onset as the standard, were compared between lesional and nonlesional groups. The specificity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography for detecting seizure onset lobe was equally high in lesional (97%) and nonlesional groups (100%), whereas sensitivity was higher in the lesional than the nonlesional group (47% versus 29%; P = 0.047). The incidence of alpha-[(11)C]methyl-l-tryptophan uptake abnormality was higher in the lesional than the nonlesional group (P < 0.01). Alpha-[(11)C]methyl-l-tryptophan positron emission tomography localized and visualized epileptogenic regions in 25% of patients with nonlocalizing magnetic resonance imaging. Although overall sensitivity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography in identifying neocortical epileptic focus is modest, specificity is extremely high. When an alpha-[(11)C]methyl-l-tryptophan focus is detected, it likely represents the epileptogenic region to be resected.382Chugani, H. T.; Kumar, A.; Kupsky, W.; Asano, E.; Sood, S.; Juhász, C. Clinical and histopathologic correlates of 11C-alpha-methyl-l-tryptophan (AMT) PET abnormalities in children with intractable epilepsy: Histopathologic correlates of AMT-PET. Epilepsia 2011, 52, 1692– 1698, DOI: 10.1111/j.1528-1167.2011.03103.x[Crossref], [PubMed], [CAS], Google Scholar382https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht12ktLzP&md5=8de99c427312dbc013c4aebc933b5adbClinical and histopathologic correlates of IIC-alpha-methyl-L-tryptophan (AMT) PET abnormalities in children with intractable epilepsyChugani, Harry T.; Kumar, Ajay; Kupsky, William; Asano, Eishi; Sood, Sandeep; Juhasz, CsabaEpilepsia (2011), 52 (9), 1692-1698CODEN: EPILAK; ISSN:0013-9580. (Wiley-Blackwell)Purpose: Interictal increase of 11C-alpha-methyl-L-tryptophan (AMT) on positron emission tomog. (PET) can be seen in cortical epileptic foci, and is particularly common in cortical developmental malformations. Therefore, in the present study, we evaluated the clin. and histopathol. correlates of AMT-PET abnormalities in children with intractable epilepsy undergoing resp. surgery. Methods: Thirty children (mean age: 6.7 ± 3.2 years) were included in this study. All patients received AMT-PET as part of their presurgical evaluation and subsequently underwent epilepsy surgery. Magnetic resonance imaging (MRI) scans were normal in 15, showed nonspecific changes in 8, and suggested malformations of cortical development (MCDs) in nine children. Asymmetry indexes (AIs) were calcd. to det. increased AMT uptake. Key Findings: Histopathol. revealed MCDs in 16 (53%) children, including 12 with cortical dysplasia (CD) [mild MCD = 3; CD type IA = 2; CD type IIA = 2 and CD type MB (severe CD with balloon cells) = 5]. Polymicrogyria and heterotopias (P&Hs) were seen in three cases and subependymal heterotopias (SEHs) in one child. The remaining 14 cases showed normal histopathol. with varying degrees of gliosis. Increased AMT uptake was found in all five with CD type MB, and all three with P&H, but in none with mild MCD and types IA-IIA CD or SEH. Whereas all five children with CD IIB and two with P&H had excellent surgical outcome (class I); children with milder CD or SEH had variable surgical outcome. The 14 patients with normal histopathol. included seven patients with focally increased and seven with normal AMT uptake. Although patients with normal pathol. and normal AMT-PET had better surgical outcome (class I = 5; II = 2), those with normal pathol., normal MRI, but abnormal AMT-PET had poor surgical outcome (class III = 4; IV = 3). Significance: Increased AMT uptake in children with CD may predict type IIB dysplasia (with balloon cells) and good surgical outcome. Histopathol. similarities between CD type IIB and epileptogenic cortical tubers may imply a common role of the inflammatory kynurenine pathway of tryptophan metab. in these lesions. In children with normal histopathol., there is a subgroup with increased AMT uptake and poor surgical outcome.383Thompson, A. J.; Metzger, S.; Lochner, M.; Ruepp, M.-D. The binding orientation of epibatidine at A7 nACh receptors. Neuropharmacology 2017, 116, 421– 428, DOI: 10.1016/j.neuropharm.2017.01.008[Crossref], [PubMed], [CAS], Google Scholar383https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslels70%253D&md5=addcf5c00648522ca36ec7e15d38e40bThe binding orientation of epibatidine at α7 nACh receptorsThompson, Andrew J.; Metzger, Simon; Lochner, Martin; Ruepp, Marc-DavidNeuropharmacology (2017), 116 (), 421-428CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)Epibatidine is an alkaloid toxin that binds with high affinity to nicotinic and muscarinic acetylcholine receptors, and has been extensively used as a research tool. To examine binding interactions at the nicotinic receptor, it has been co-crystd. with the structural homolog acetylcholine binding protein (AChBP; PDB ID 2BYQ), and with an AChBP chimaera (3SQ6) that shares 64% sequence identity with the α7 nACh receptor. However, the binding orientations revealed by AChBP co-crystal structures may not precisely represent their receptor homologues and exptl. evidence is needed to verify the ligand poses. Here we identify potential binding site interactions between epibatidine and AChBP residues, and substitute equiv. positions in the α7 nACh receptor. The effects of these are probed by [3H]epibatidine binding following the expression α7 nACh receptor cysteine mutants in HEK 293 cells. Of the sixteen mutants created, the affinity of epibatidine was unaffected by the substitutions Q55C, L106C, L116C, T146C, D160C and S162C, reduced by C186A and C187A, increased by Q114C and S144C, and abolished by W53C, Y91C, N104C, W145C, Y184C and Y191C. These results are consistent with the predicted orientations in AChBP and suggest that epibatidine is likely to occupy a similar location at α7 nACh receptors. We speculate that steric constraints placed upon the C-5 position of the pyridine ring in 3SQ6 may account for the relatively poor affinities of epibatidine derivs. that are substituted at this position.384Wong, D. F.; Kuwabara, H.; Pomper, M.; Holt, D. P.; Brasic, J. R.; George, N.; Frolov, B.; Willis, W.; Gao, Y.; Valentine, H.; Nandi, A.; Gapasin, L.; Dannals, R. F.; Horti, A. G. Human brain imaging of A7 nAChR with [18F]ASEM: A new PET radiotracer for neuropsychiatry and determination of drug occupancy. Mol. Imaging Biol. 2014, 16, 730– 738, DOI: 10.1007/s11307-014-0779-3[Crossref], [PubMed], [CAS], Google Scholar384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252Fkt1Ghug%253D%253D&md5=3cf858ba37824e3fe52efcbaae0d6572Human brain imaging of α7 nAChR with [(18)F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancyWong Dean F; Kuwabara Hiroto; Pomper Martin; Holt Daniel P; Brasic James R; George Noble; Frolov Boris; Willis William; Gao Yongjun; Valentine Heather; Nandi Ayon; Gapasin Lorena; Dannals Robert F; Horti Andrew GMolecular imaging and biology (2014), 16 (5), 730-8 ISSN:.PURPOSE: Using the α7-nAChR radiotracer, [(18)F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer. PROCEDURES: Five healthy male subjects were imaged for 90 min following IV [(18)F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [(18)F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding. RESULTS: [(18)F]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [(18)F]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (>20 ml/ml) and binding potentials >1 with TRV averaged 10.8 ± 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two α7-nAChR drugs. CONCLUSIONS: The characteristics of [(18)F]ASEM are consistent with the ability to quantify α7-nAChR in the human brain. [(18)F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential α7-nAChR drugs.385Horti, A. G. Development of [(18)F]ASEM, a specific radiotracer for quantification of the A7-nAChR with positron-emission tomography. Biochem. Pharmacol. 2015, 97, 566– 575, DOI: 10.1016/j.bcp.2015.07.030[Crossref], [PubMed], [CAS], Google Scholar385https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Oqt7vN&md5=1cf3d50ab569d38a65bec2d097d6c56fDevelopment of [18F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomographyHorti, A. G.Biochemical Pharmacology (Amsterdam, Netherlands) (2015), 97 (4), 566-575CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)A review. The alpha-7 subtype of the nicotinic acetylcholine receptor (α7-nAChR) is fundamental to physiol.; it mediates various brain functions and represents an important target for drug discovery. Exploration of the brain nicotinic acetylcholine receptors (nAChRs) using positron-emission tomog. (PET) will make it possible to better understand the important role of this receptor and to study its involvement in schizophrenia, bipolar disorder, Alzheimer's and Parkinson's diseases, drug dependence, inflammation and many other disorders and simplify the development of nicotinic drugs for treatment of these disorders. Until recently, PET imaging of α7-nAChRs has been impeded by the absence of good radiotracers. This review describes various endeavors to develop α7-nAChR PET tracers by several research groups including the author's group. Most initial PET tracers for imaging α7-nAChRs did not exhibit suitable imaging properties due to their low specific binding. Newly discovered [18F]ASEM is the first highly specific α7-nAChR radioligand and in 2014 it was translated to human PET imaging.386Zubieta, J. K.; Koeppe, R. A.; Frey, K. A.; Kilbourn, M. R.; Mangner, T. J.; Foster, N. L.; Kuhl, D. E. Assessment of muscarinic receptor concentrations in aging and Alzheimer disease with [11C]NMPB and PET. Synapse 2001, 39, 275– 287, DOI: 10.1002/1098-2396(20010315)39:4<275::AID-SYN1010>3.0.CO;2-3[Crossref], [PubMed], [CAS], Google Scholar386https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhtVGntb8%253D&md5=59fcb4d5a8eab599343a983374280739Assessment of muscarinic receptor concentrations in aging and Alzheimer disease with [11C]NMPB and PETZubieta, Jon-Kar; Koeppe, Robert A.; Frey, Kirk A.; Kilbourn, Michael R.; Mangner, Thomas J.; Foster, Norman L.; Kuhl, David E.Synapse (New York) (2001), 39 (4), 275-287CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)Cerebral cholinergic deficits have been described in Alzheimer disease (AD) and as a result of normal aging. At the present time, there are very limited options for the quantification of cholinergic receptors with in vivo imaging techniques such as PET. In the present study, we examd. the feasibility of utilizing [11C]N-methyl-4-piperidyl benzilate (NMPB), a nonselective muscarinic receptor ligand, in the study of aging and neurodegenerative processes assocd. with cholinergic dysfunction. Based on prior data describing the accuracy of various kinetic methods, we examd. the concn. of muscarinic receptors with [11C]NMPB and PET using two- and three- compartment kinetic models. Eighteen healthy subjects and six patients diagnosed with probable AD were studied. Pixel-by-pixel two-compartment model fits showed acceptable precision in the study of normal aging, with comparable results to those obtained with a more complex and less precise three-compartment model. Normal aging was assocd. with a redn. in muscarinic receptor binding in neocortical regions and thalamus. In AD patients, the three-compartment model appeared capable of dissocg. changes in tracer transport from changes in receptor binding, but suffered from statistical uncertainty, requiring normalization to a ref. region, and therefore limiting its potential use in the study of neurodegenerative processes. After normalization, no regional changes in muscarinic receptor concns. were obsd. in AD.387Asahina, M.; Suhara, T.; Shinotoh, H.; Inoue, O.; Suzuki, K.; Hattori, T. Brain muscarinic receptors in progressive supranuclear palsy and Parkinson’s disease: A positron emission tomographic study. J. Neurol., Neurosurg. Psychiatry 1998, 65, 155– 163, DOI: 10.1136/jnnp.65.2.155[Crossref], [PubMed], [CAS], Google Scholar387https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1czms1Ohtg%253D%253D&md5=aa4e24971e6dcf287f06236c9e9bbe94Brain muscarinic receptors in progressive supranuclear palsy and Parkinson's disease: a positron emission tomographic studyAsahina M; Suhara T; Shinotoh H; Inoue O; Suzuki K; Hattori TJournal of neurology, neurosurgery, and psychiatry (1998), 65 (2), 155-63 ISSN:0022-3050.OBJECTIVES: To assess muscarinic acetylcholine receptors (mAChRs) in the brains of patients with progressive supranuclear palsy and Parkinson's disease, and to correlate the cholinergic system with cognitive function in progressive supranuclear palsy and Parkinson's disease. METHODS: Positron emission tomography (PET) and [11C]N-methyl-4-piperidyl benzilate ([11C]NMPB) was used to measure mAChRs in the brain of seven patients with progressive supranuclear palsy, 12 patients with Parkinson's disease, and eight healthy controls. All of the patients with progressive supranuclear palsy were demented. The Parkinson's disease group consisted of 11 non-demented patients and one demented patient. The mini mental state examination (MMSE) was used to assess the severity of cognitive dysfunction in all of the subjects. The modified Wisconsin card sorting test (WCST) was used to evaluate frontal cognitive function in the non-demented patients with Parkinson's disease and controls. RESULTS: The mean K3 value, an index of mAChR binding, was significantly higher for the frontal cortex in the patients with Parkinson's disease than in the controls (p<0.01). By contrast, the patients with progressive supranuclear palsy had no significant changes in the K3 values of any cerebral cortical regions. The mean score of the MMSE in the progressive supranuclear palsy group was significantly lower than that in the control group. Although there was no difference between the Parkinson's disease and control groups in the MMSE, the non-demented patients with Parkinson's disease showed significant frontal lobe dysfunction in the WCST. CONCLUSIONS: The increased mAChR binding in the frontal cortex of the patients with Parkinson's disease may reflect denervation hypersensitivity caused by loss of the ascending cholinergic input to that region from the basal forebrain and may be related to frontal lobe dysfunction in Parkinson's disease. The cerebral cortical cholinergic system may not have a major role in cognitive dysfunction in progressive supranuclear palsy.388Pappata, S.; Tavitian, B.; Traykov, L.; Jobert, A.; Dalger, A.; Mangin, J. F.; Crouzel, C.; DiGiamberardino, L. In vivo imaging of human cerebral acetylcholinesterase. J. Neurochem. 1996, 67, 876– 879, DOI: 10.1046/j.1471-4159.1996.67020876.x[Crossref], [PubMed], [CAS], Google Scholar388https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XksFCjtbs%253D&md5=38bfe3946ffe3bd7007f6ec269602a04In vivo imaging of human cerebral acetylcholinesterasePappata, S.; Tavitian, B.; Traykov, L.; Jobert, A.; Dalger, A.; Mangin, J. F.; Crouzel, C.; Di Giamberardino, L.Journal of Neurochemistry (1996), 67 (2), 876-879CODEN: JONRA9; ISSN:0022-3042. (Lippincott-Raven)We report here the first positron emission tomog. (PET) images showing the in vivo regional distribution of acetylcholinesterase (AChE) in human brain. The study was carried out in eight healthy human volunteers using as a tracer [11C]-physostigmine ([11C]PHY), an inhibitor of AChE. After i.v. injection of [11C]PHY, radioactivity was rapidly taken up in brain tissue and reached maximal uptake within a few minutes, following a regional pattern mostly related to cerebral perfusion. After the peak, the cerebral radioactivity gradually decreased with a half-life varying from 20 to 35 min, depending on the brain structure. [11C]PHY retention was higher in regions rich in AChE, such as the striatum (half-life, 35 min), than in regions poor in AChE, such as the cerebral cortex (half-life, 20 min). At later times (25-35 min postinjection), the cerebral distribution of [11C]PHY was typical of AChE activity: putamen-caudate > cerebellum > brainstem > thalamus > cerebral cortex, with a striatal to cortex ratio of 2. These results suggest that PET studies with [11C]PHY can provide in vivo brain mapping of human AChE and are promising for the study of changes in AChE levels assocd. with neurodegenerative diseases.389Herholz, K. Acetylcholine esterase activity in mild cognitive impairment and Alzheimer’s Disease. Eur. J. Nucl. Med. Mol. Imaging 2008, 35 (S1), 25– 29, DOI: 10.1007/s00259-007-0699-4[Crossref], [CAS], Google Scholar389https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlsFOitLY%253D&md5=613218420bb4f2bc667fdfe675a30c4bAcetylcholine esterase activity in mild cognitive impairment and Alzheimer's diseaseHerholz, KarlEuropean Journal of Nuclear Medicine and Molecular Imaging (2008), 35 (Suppl. 1), S25-S29CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. Purpose: Impairment of cholinergic neurotransmission is a well-established fact in Alzheimer's disease (AD), but there is controversy about its relevance at the early stages of the disease and in mild cognitive impairment (MCI). Methods: In vivo positron emission tomog. imaging of cortical acetylcholine esterase (AChE) activity as a marker of cholinergic innervation that is expressed by cholinergic axons and cholinoceptive neurons has demonstrated a redn. of this enzyme activity in manifest AD. The technique is also useful to measure the inhibition of cerebral AChE induced by cholinesterase inhibitors for treatment of dementia symptoms. Results: A redn. of cortical AchE activity was found consistently in all studies of AD and in few cases of MCI who later concerted to AD. Conclusion: The in vivo findings in MCI and very mild AD are still preliminary, and studies seem to suggest that cholinergic innervation and AChE as the main degrading enzyme are both reduced, which might result in partial compensation of their effect.390Mathis, C. A.; Bacskai, B. J.; Kajdasz, S. T.; McLellan, M. E.; Frosch, M. P.; Hyman, B. T.; Holt, D. P.; Wang, Y.; Huang, G.-F.; Debnath, M. L.; Klunk, W. E. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg. Med. Chem. Lett. 2002, 12, 295– 298, DOI: 10.1016/S0960-894X(01)00734-X[Crossref], [PubMed], [CAS], Google Scholar390https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpslKmtQ%253D%253D&md5=c761b7a60b9ec39bdf615c28983a89e0A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brainMathis, Chester A.; Bacskai, Brian J.; Kajdasz, Stephen T.; McLellan, Megan E.; Frosch, Matthew P.; Hyman, Bradley T.; Holt, Daniel P.; Wang, Yanming; Huang, Guo-Feng; Debnath, Manik L.; Klunk, William E.Bioorganic & Medicinal Chemistry Letters (2002), 12 (3), 295-298CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The synthesis of a new lipophilic thioflavin-T analog, 2-[4-(methylamino)phenyl]benzothiazole (I), with high affinity for amyloid is reported. I.v. injection of [11C]-labeled I into control mice resulted in high brain uptake. Amyloid deposits were imaged with multiphoton microscopy in the brains of living transgenic mice following the systemic injection of unlabeled I. [11C]-I is a promising amyloid imaging agent for Alzheimer's disease.391Grimmer, T.; Shi, K.; Diehl-Schmid, J.; Natale, B.; Drzezga, A.; Förster, S.; Förstl, H.; Schwaiger, M.; Yakushev, I.; Wester, H.-J.; Kurz, A.; Yousefi, B. H. Correction: 18F-FIBT may expand PET for β-amyloid imaging in neurodegenerative diseases. Mol. Psychiatry 2020, 25, 2608– 2619, DOI: 10.1038/s41380-018-0203-5[Crossref], [PubMed], [CAS], Google Scholar391https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFCktbzL&md5=0af5e6b6cbc45cfeb0547e22eb93333418F-FIBT may expand PET for β-amyloid imaging in neurodegenerative diseasesGrimmer, Timo; Shi, Kuangyu; Diehl-Schmid, Janine; Natale, Bianca; Drzezga, Alexander; Foerster, Stefan; Foerstl, Hans; Schwaiger, Markus; Yakushev, Igor; Wester, Hans-Juergen; Kurz, Alexander; Yousefi, Behrooz HooshyarMolecular Psychiatry (2020), 25 (10), 2608-2619CODEN: MOPSFQ; ISSN:1359-4184. (Nature Research)18F-FIBT, 2-(p-Methylaminophenyl)-7-(2-[18F]fluoroethoxy)imidazo-[2,1-b]benzothiazole, is a new selective PET tracer under clin. investigation to specifically image β-amyloid depositions (Aβ) in humans in-vivo that binds to Aβ with excellent affinity (Kd 0.7 ± 0.2) and high selectivity over tau and α-synuclein aggregates (Ki > 1000 nM). We aimed to characterize 18F-FIBT in a series of patients with different clin.-pathophysiol. phenotypes and to compare its binding characteristics to the ref. compd. PiB. Six patients (mild late-onset and moderate early-onset AD dementia, mild cognitive impairment due to AD, intermediate likelihood, mild behavioral variant of frontotemporal dementia, subjective memory impairment without evidence of neurodegeneration, and mild dementia due to Posterior Cortical Atrophy) underwent PET imaging with 18F-FIBT on PET/MR. SUVR showed the highest correlation with clin. severity. The previous preclin. characterization and the results of this case series suggest the clin. usefulness of FIBT as a selective and highly affine next-generation 18F-labeled tracer for amyloid-imaging with excellent pharmacokinetics in the diagnosis of neurodegenerative diseases. The results compare well to the gold std. PiB and hence support further investigation in larger human samples.392Richards, D.; Sabbagh, M. N. Florbetaben for PET imaging of beta-amyloid plaques in the brain. Neurol Ther. 2014, 3, 79– 88, DOI: 10.1007/s40120-014-0022-9[Crossref], [PubMed], [CAS], Google Scholar392https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfmsFWrsw%253D%253D&md5=473d2268da9f93443d7b9e1f3c843209Florbetaben for PET Imaging of Beta-Amyloid Plaques in the BrainRichards Danielle; Sabbagh Marwan NNeurology and therapy (2014), 3 (2), 79-88 ISSN:2193-8253.Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting the elderly. Current clinical diagnostic tools are often ineffective in accurately diagnosing AD. However, new advances in diagnostic imaging, particularly positron emission tomography (PET) amyloid imaging, have shown increased sensitivity and specificity, as well as high inter-reader agreement. The most commonly studied tracer, PiB-C11, has shown high affinity binding to amyloid, but is limited in its use outside of research due to its short half-life. Instead, development of other PET ligands with increased half-life, such as fluorine-18-labeled ((18)F) tracers, allows for more widespread use of PET in clinical settings. In particular, recent phase II and III trials of (18)F-florbetaben have demonstrated the high accuracy of this PET tracer in identifying amyloid accumulation. This paper will examine the techniques of amyloid imaging, focusing particularly on the recently approved (18)F-florbetaben.393Klunk, W. E.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; Holt, D. P.; Bergström, M.; Savitcheva, I.; Huang, G.; Estrada, S.; Ausén, B.; Debnath, M. L.; Barletta, J.; Price, J. C.; Sandell, J.; Lopresti, B. J.; Wall, A.; Koivisto, P.; Antoni, G.; Mathis, C. A.; Långström, B. Imaging brain amyloid in Alzheimer’s Disease with Pittsburgh compound-B. Ann. Neurol. 2004, 55, 306– 319, DOI: 10.1002/ana.20009[Crossref], [PubMed], [CAS], Google Scholar393https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisFKntb8%253D&md5=3e036dca56dcb81e0cf131a5b100f95fImaging brain amyloid in Alzheimer's disease with Pittsburgh compound-BKlunk, William E.; Engler, Henry; Nordberg, Agneta; Wang, Yanming; Blomqvist, Gunnar; Holt, Daniel P.; Bergstrom, Mats; Savitcheva, Irina; Huang, Guo-feng; Estrada, Sergio; Ausen, Birgitta; Debnath, Manik L.; Barletta, Julien; Price, Julie C.; Sandell, Johan; Lopresti, Brian J.; Wall, Anders; Koivisto, Pernilla; Antoni, Gunnar; Mathis, Chester A.; Langstrom, BengtAnnals of Neurology (2004), 55 (3), 306-319CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)This report describes the first human study of a novel amyloid-imaging positron emission tomog. (PET) tracer, termed Pittsburgh Compd.-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of assocn. cortex known to contain large amts. of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were obsd. in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equiv. in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 yr) and six older healthy controls (69.5±11 yr) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metab. detd. with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quant. information on amyloid deposits in living subjects.394Wolk, D. A.; Zhang, Z.; Boudhar, S.; Clark, C. M.; Pontecorvo, M. J.; Arnold, S. E. Amyloid imaging in Alzheimer’s disease: Comparison of florbetapir and Pittsburgh compound-B positron emission tomography. J. Neurol., Neurosurg. Psychiatry 2012, 83, 923– 926, DOI: 10.1136/jnnp-2012-302548[Crossref], [PubMed], [CAS], Google Scholar394https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jpslCrug%253D%253D&md5=930cb64494f5292f869e9f01e5463e62Amyloid imaging in Alzheimer's disease: comparison of florbetapir and Pittsburgh compound-B positron emission tomographyWolk David A; Zhang Zheng; Boudhar Sanaa; Clark Christopher M; Pontecorvo Michael J; Arnold Steven EJournal of neurology, neurosurgery, and psychiatry (2012), 83 (9), 923-6 ISSN:.BACKGROUND: Amyloid imaging provides in vivo detection of the fibrillar amyloid-β (Aβ) plaques of Alzheimer's disease (AD). The positron emission tomography (PET) ligand, Pittsburgh Compound-B (PiB-C11), is the most well studied amyloid imaging agent, but the short half-life of carbon-11 limits its clinical viability. Florbetapir-F18 recently demonstrated in vivo correlation with postmortem Aβ histopathology, but has not been directly compared with PiB-C11. METHODS: Fourteen cognitively normal adults and 12 AD patients underwent PiB-C11 and florbetapir-F18 PET scans within a 28-day period. RESULTS: Both ligands displayed highly significant group discrimination and correlation of regional uptake. CONCLUSION: These data support the hypothesis that florbetapir-F18 provides comparable information with PiB-C11.395Vandenberghe, R.; Van Laere, K.; Ivanoiu, A.; Salmon, E.; Bastin, C.; Triau, E.; Hasselbalch, S.; Law, I.; Andersen, A.; Korner, A.; Minthon, L.; Garraux, G.; Nelissen, N.; Bormans, G.; Buckley, C.; Owenius, R.; Thurfjell, L.; Farrar, G.; Brooks, D. J. 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial. Ann. Neurol. 2010, 68, 319– 329, DOI: 10.1002/ana.22068[Crossref], [PubMed], [CAS], Google Scholar395https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cjpsleisg%253D%253D&md5=1cef58b91f2f25d7d48fef9d352c64b018F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trialVandenberghe Rik; Van Laere Koen; Ivanoiu Adrian; Salmon Eric; Bastin Christine; Triau Eric; Hasselbalch Steen; Law Ian; Andersen Allan; Korner Alex; Minthon Lennart; Garraux Gaetan; Nelissen Natalie; Bormans Guy; Buckley Chris; Owenius Rikard; Thurfjell Lennart; Farrar Gill; Brooks David JAnnals of neurology (2010), 68 (3), 319-29 ISSN:.OBJECTIVE: The most widely studied positron emission tomography ligand for in vivo beta-amyloid imaging is (11)C-Pittsburgh compound B ((11)C-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the (18)F-labeled PIB derivative (18)F-flutemetamol could significantly enhance access to this novel technology. METHODS: Twenty-seven patients with early-stage clinically probable Alzheimer disease (AD), 20 with amnestic mild cognitive impairment (MCI), and 15 cognitively intact healthy volunteers (HVs) above and 10 HVs below 55 years of age participated. The primary endpoint was the efficacy of blinded visual assessments of (18)F-flutemetamol scans in assigning subjects to a raised versus normal uptake category, with clinical diagnosis as the standard of truth (SOT). As secondary objectives, we determined the correlation between the regional standardized uptake value ratios (SUVRs) for (18)F-flutemetamol and its parent molecule (11)C-PIB in 20 of the AD subjects and 20 of the MCI patients. We also determined test-retest variability of (18)F-flutemetamol SUVRs in 5 of the AD subjects. RESULTS: Blinded visual assessments of (18)F-flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical (18)F-flutemetamol SUVRs and (11)C-PIB SUVRs ranged from 0.89 to 0.92. Test-retest variabilities of regional SUVRs were 1 to 4%. INTERPRETATION: (18)F-Flutemetamol performs similarly to the (11)C-PIB parent molecule within the same subjects and provides high test-retest replicability and potentially much wider accessibility for clinical and research use.396Rowe, C. C.; Villemagne, V. L. Brain amyloid imaging. J. Nucl. Med. Technol. 2013, 41, 11– 18, DOI: 10.2967/jnumed.110.076315[Crossref], [PubMed], [CAS], Google Scholar396https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3szntVKqsw%253D%253D&md5=da2dbc87cdcb299789fed14f7a1848b0Brain amyloid imagingRowe Christopher C; Villemagne Victor LJournal of nuclear medicine technology (2013), 41 (1), 11-8 ISSN:.Imaging of brain β-amyloid plaques with (18)F-labeled tracers for PET will likely be available in clinical practice to assist the diagnosis of Alzheimer disease (AD). With the rapidly growing prevalence of AD as the population ages, and the increasing emphasis on early diagnosis and treatment, brain amyloid imaging is set to become a widely performed investigation. All physicians reading PET scans will need to know the complex relationship between amyloid and cognitive decline, how to best acquire and display images for detection of amyloid, and how to recognize the patterns of tracer binding in AD and other causes of dementia. This article will provide nuclear medicine physicians with the background knowledge required for understanding this emerging investigation, including its appropriate use, and prepare them for practical training in scan interpretation.397Verhoeff, N. P. L. G. In-Vivo imaging of Alzheimer disease -amyloid with [11C]SB-13 PET. American Journal of Geriatric Psychiatry. 2004, 12, 584– 595, DOI: 10.1176/appi.ajgp.12.6.584[Crossref], [PubMed], [CAS], Google Scholar397https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cngtFOnsg%253D%253D&md5=2bcdcbabeecdb1c3668ea2d01bda5ac3In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PETVerhoeff Nicolaas P L G; Wilson Alan A; Takeshita Shinichiro; Trop Liat; Hussey Doug; Singh Kernjit; Kung Hank F; Kung Mei-Ping; Houle SylvainThe American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry (2004), 12 (6), 584-95 ISSN:1064-7481.OBJECTIVE: In-vivo imaging of beta-amyloid plaques (Abeta) may improve both early detection of Alzheimer disease (AD) and efficacy assessment of new treatments for AD. The authors' aim was to develop a novel Abeta-specific positron-emission tomography (PET) tracer. METHODS: Five female AD patients (54-77 years old) and six healthy female comparison subjects (53-74 years old), completed 2-hour PET scans after intravenous injection of 10 mCi of both the stilbene [11C]SB-13 and the benzothiazole [11C]6-OH-BTA-1 (also known as [11C]PIB). Kinetic analyses were performed on the resulting time-activity curves to derive Abeta binding-potential estimates, using as input function either the unmetabolized tracer concentration in venous plasma from a two-tissue compartment model or the density of radioactivity in the cerebellum. Authors compared the binding characteristics of the two radiotracers. RESULTS: The two radiotracers demonstrated similar binding properties with respect to regional distribution of retention (increased retention in the frontal and posterior temporal-inferior parietal association cortices in the AD patients, but not in the comparison subjects). Our preliminary PET data indicate that [11C]SB-13 may be similar to [11C]PIB in discriminating AD patients from comparison subjects. CONCLUSIONS: [11C]SB-13 is an effective PET tracer for fibrillar Abeta imaging in vivo, with similar performance as [11C]PIB. Future research directions include evaluation of tracer in larger AD patient samples and in subjects with amnestic mild cognitive impairment, evaluation of arterial input function, and comparison with other tracers, such as [18F]FDG as they relate to cognitive functioning.398Buée, L.; Bussière, T.; Buée-Scherrer, V.; Delacourte, A.; Hof, P. R. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Rev. 2000, 33, 95– 130, DOI: 10.1016/S0165-0173(00)00019-9[Crossref], [PubMed], [CAS], Google Scholar398https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtVCrtbY%253D&md5=d51d14c9e8b56e9661db4ae4afc2c943Tau protein isoforms, phosphorylation and role in neurodegenerative disordersBuee, L.; Bussiere, T.; Buee-Scherrer, V.; Delacourte, A.; Hof, P. R.Brain Research Reviews (2000), 33 (1), 95-130CODEN: BRERD2; ISSN:0165-0173. (Elsevier Science B.V.)A review, with 425 refs. Tau proteins belong to the family of microtubule-assocd. proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intra-neuronal and glial fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Mol. anal. has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathol. tau proteins exhibiting a typical biochem. pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathol. tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.399Lois, C.; Gonzalez, I.; Johnson, K. A.; Price, J. C. PET imaging of tau protein targets: A methodology perspective. Brain Imaging and Behavior. 2019, 13, 333– 344, DOI: 10.1007/s11682-018-9847-7[Crossref], [PubMed], [CAS], Google Scholar399https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MrntVagtg%253D%253D&md5=b83e6256f07ebfedf37a2e78748fe5d9PET imaging of tau protein targets: a methodology perspectiveLois Cristina; Johnson Keith A; Gonzalez Ivan; Price Julie CBrain imaging and behavior (2019), 13 (2), 333-344 ISSN:.The two neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-[Formula: see text] plaques and neurofibrillary tangles of tau protein. Fifteen years ago, Positron Emission Tomography (PET) with Pittsburgh Compound B ((11)C-PiB) enabled selective in-vivo visualization of amyloid-[Formula: see text] plaque deposits and has since provided valuable information about the role of amyloid-[Formula: see text] deposition in AD. The progression of tau deposition has been shown to be highly associated with neuronal loss, neurodegeneration, and cognitive decline. Until recently it was not possible to visualize tau deposition in-vivo, but several tau PET tracers are now available in different stages of clinical development. To date, no tau tracer has been approved by the Food and Drug Administration for use in the evaluation of AD or other tauopathies, despite very active research efforts. In this paper we review the recent developments in tau PET imaging with a focus on in-vivo findings in AD and discuss the challenges associated with tau tracer development, the status of development and validation of different tau tracers, and the clinical information these provide.400Giannakopoulos, P.; Herrmann, F. R.; Bussière, T.; Bouras, C.; Kövari, E.; Perl, D. P.; Morrison, J. H.; Gold, G.; Hof, P. R. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 2003, 60, 1495– 1500, DOI: 10.1212/01.WNL.0000063311.58879.01[Crossref], [PubMed], [CAS], Google Scholar400https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s3it1Sqtg%253D%253D&md5=7269baa47ff91be1243c2d7648335dd9Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's diseaseGiannakopoulos P; Herrmann F R; Bussiere T; Bouras C; Kovari E; Perl D P; Morrison J H; Gold G; Hof P RNeurology (2003), 60 (9), 1495-500 ISSN:.OBJECTIVE: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. BACKGROUND: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. METHODS: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. RESULTS: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. CONCLUSIONS: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.401Okamura, N.; Suemoto, T.; Furumoto, S.; Suzuki, M.; Shimadzu, H.; Akatsu, H.; Yamamoto, T.; Fujiwara, H.; Nemoto, M.; Maruyama, M.; Arai, H.; Yanai, K.; Sawada, T.; Kudo, Y. Quinoline and benzimidazole derivatives: Candidate probes for in vivo imaging of tau pathology in Alzheimer’s disease. J. Neurosci. 2005, 25, 10857– 10862, DOI: 10.1523/JNEUROSCI.1738-05.2005[Crossref], [PubMed], [CAS], Google Scholar401https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yks77K&md5=4b0bc18420a2429789d47bcb91eeb11cQuinoline and benzimidazole derivatives: Candidate probes for in vivo imaging of tau pathology in Alzheimer's diseaseOkamura, Nobuyuki; Suemoto, Takahiro; Furumoto, Shozo; Suzuki, Masako; Shimadzu, Hiroshi; Akatsu, Hiroyasu; Yamamoto, Takayuki; Fujiwara, Hironori; Nemoto, Miyako; Maruyama, Masahiro; Arai, Hiroyuki; Yanai, Kazuhiko; Sawada, Tohru; Kudo, YukitsukaJournal of Neuroscience (2005), 25 (47), 10857-10862CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Neurofibrillary tangles (NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathol. characteristics of Alzheimer's disease (AD). These lesions occur before the presentation of clin. symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclin. diagnosis of AD and for tracking disease progression. The present study introduces three novel compds., 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine (BF-126), 2-[(4-methylamino)phenyl]quinoline (BF-158), and 2-(4-aminophenyl)quinoline (BF-170), as candidate probes for in vivo imaging of tau pathol. in the AD brain. When solns. of these compds. are injected i.v. into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compds. display relatively lower binding affinity to β-amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathol. examn. using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiog. using 11C-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivs. for in vivo imaging of tau pathol. in AD.402Fodero-Tavoletti, M. T.; Okamura, N.; Furumoto, S.; Mulligan, R. S.; Connor, A. R.; McLean, C. A.; Cao, D.; Rigopoulos, A.; Cartwright, G. A.; O’Keefe, G.; Gong, S.; Adlard, P. A.; Barnham, K. J.; Rowe, C. C.; Masters, C. L.; Kudo, Y.; Cappai, R.; Yanai, K.; Villemagne, V. L. 18F-THK523: A novel in vivo tau imaging ligand for Alzheimer’s disease. Brain 2011, 134, 1089– 1100, DOI: 10.1093/brain/awr038[Crossref], [PubMed], [CAS], Google Scholar402https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MvgsVejsA%253D%253D&md5=4c6954ff8eed443bb6eaf040ffb88d3818F-THK523: a novel in vivo tau imaging ligand for Alzheimer's diseaseFodero-Tavoletti Michelle T; Okamura Nobuyuki; Furumoto Shozo; Mulligan Rachel S; Connor Andrea R; McLean Catriona A; Cao Diana; Rigopoulos Angela; Cartwright Glenn A; O'Keefe Graeme; Gong Sylvia; Adlard Paul A; Barnham Kevin J; Rowe Christopher C; Masters Colin L; Kudo Yukitsuka; Cappai Roberto; Yanai Kazuhiko; Villemagne Victor LBrain : a journal of neurology (2011), 134 (Pt 4), 1089-100 ISSN:.While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.403Villemagne, V. L.; Furumoto, S.; Fodero-Tavoletti, M. T.; Mulligan, R. S.; Hodges, J.; Kudo, Y.; Masters, C. L.; Yanai, K.; Rowe, C. C.; Okamura, N. In vivo tau imaging in Alzheimer’s disease. J. Nucl. Med. 2012, 53 (Suppl. 2), 111P404Shao, X.; Carpenter, G. M.; Desmond, T. J.; Sherman, P.; Quesada, C. A.; Fawaz, M.; Brooks, A. F.; Kilbourn, M. R.; Albin, R. L.; Frey, K. A.; Scott, P. J. H. Evaluation of [11C] N -methyl lansoprazole as a radiopharmaceutical for PET imaging of tau neurofibrillary tangles. ACS Med. Chem. Lett. 2012, 3, 936– 941, DOI: 10.1021/ml300216t[ACS Full Text], [CAS], Google Scholar404https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtl2lsr%252FI&md5=a1fd3561aca6b2d9366271582e9bf60fEvaluation of [11C]N-Methyl Lansoprazole as a Radiopharmaceutical for PET Imaging of Tau Neurofibrillary TanglesShao, Xia; Carpenter, Garrett M.; Desmond, Timothy J.; Sherman, Phillip; Quesada, Carole A.; Fawaz, Maria; Brooks, Allen F.; Kilbourn, Michael R.; Albin, Roger L.; Frey, Kirk A.; Scott, Peter J. H.ACS Medicinal Chemistry Letters (2012), 3 (11), 936-941CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)[11C]N-Me lansoprazole ([11C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomog. (PET) imaging. [11C]NML was synthesized from com. available lansoprazole in 4.6% radiochem. yield (noncorrected RCY, based upon [11C]MeI), 99% radiochem. purity, and 16095 Ci/mmol specific activity (n = 5). Log P was detd. to be 2.18. A lack of brain uptake in rodent microPET imaging revealed [11C]NML to be a substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by pretreating with cyclosporin A to block the PGP. Contrastingly, [11C]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [11C]NML uptake in the healthy primate brain of ∼1600 nCi/cc max. at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiog. between wild-type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [11C]NML in the cortex of brains expressing human tau. Further autoradiog. with tau pos. brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [11C]NML with tau NFTs identified using modified Bielschowsky staining. Finally, satn. binding expts. with heparin-induced tau confirmed Kd and Bmax values of [11C]NML as 700 pM and 0.214 fmol/μg, resp.405Gobbi, L. C.; Knust, H.; Körner, M.; Honer, M.; Czech, C.; Belli, S.; Muri, D.; Edelmann, M. R.; Hartung, T.; Erbsmehl, I.; Grall-Ulsemer, S.; Koblet, A.; Rueher, M.; Steiner, S.; Ravert, H. T.; Mathews, W. B.; Holt, D. P.; Kuwabara, H.; Valentine, H.; Dannals, R. F.; Wong, D. F.; Borroni, E. Identification of three novel radiotracers for imaging aggregated tau in Alzheimer’s disease with positron emission tomography. J. Med. Chem. 2017, 60, 7350– 7370, DOI: 10.1021/acs.jmedchem.7b00632[ACS Full Text], [CAS], Google Scholar405https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVOnsL7N&md5=599042bc3d648b54b2bad36aa6ec43baIdentification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission TomographyGobbi, Luca C.; Knust, Henner; Korner, Matthias; Honer, Michael; Czech, Christian; Belli, Sara; Muri, Dieter; Edelmann, Martin R.; Hartung, Thomas; Erbsmehl, Isabella; Grall-Ulsemer, Sandra; Koblet, Andreas; Rueher, Marianne; Steiner, Sandra; Ravert, Hayden T.; Mathews, William B.; Holt, Daniel P.; Kuwabara, Hiroto; Valentine, Heather; Dannals, Robert F.; Wong, Dean F.; Borroni, EdilioJournal of Medicinal Chemistry (2017), 60 (17), 7350-7370CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aggregates of tau and beta amyloid (Aβ) plaques constitute the histopathol. hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathol. forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aβ plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.406Turkheimer, F. E.; Rizzo, G.; Bloomfield, P. S.; Howes, O.; Zanotti-Fregonara, P.; Bertoldo, A.; Veronese, M. The methodology of TSPO imaging with positron emission tomography. Biochem. Soc. Trans. 2015, 43, 586– 592, DOI: 10.1042/BST20150058[Crossref], [PubMed], [CAS], Google Scholar406https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVCrsbzI&md5=e3086036c65c8ade42b65caa585e5e75The methodology of TSPO imaging with positron emission tomographyTurkheimer, Federico E.; Rizzo, Gaia; Bloomfield, Peter S.; Howes, Oliver; Zanotti-Fregonara, Paolo; Bertoldo, Alessandra; Veronese, MattiaBiochemical Society Transactions (2015), 43 (4), 586-592CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)A review. The 18-kDA translocator protein (TSPO) is consistently elevated in activated microglia of the central nervous system (CNS) in response to a variety of insults as well as neurodegenerative and psychiatric conditions. It is therefore a target of interest for mol. strategies aimed at imaging neuroinflammation in vivo. For more than 20 years, positron emission tomog. (PET) has allowed the imaging of TSPO d. in brain using [11C]-(R)-PK11195, a radiolabeled-specific antagonist of the TSPO that has demonstrated microglial activation in a large no. pathol. cohorts. The significant clin. interest in brain immunity as a primary or comorbid factor in illness has sparked great interest in the TSPO as a biomarker and a surprising no. of second generation TSPO radiotracers have been developed aimed at improving the quality of TSPO imaging through novel radioligands with higher affinity. However, such major investment has not yet resulted in the expected improvement in image quality. We here review the main methodol. aspects of TSPO PET imaging with particular attention to TSPO genetics, cellular heterogeneity of TSPO in brain tissue and TSPO distribution in blood and plasma that need to be considered in the quantification of PET data to avoid spurious results as well as ineffective development and use of these radiotracers.407Gershen, L. D.; Zanotti-Fregonara, P.; Dustin, I. H.; Liow, J.-S.; Hirvonen, J.; Kreisl, W. C.; Jenko, K. J.; Inati, S. K.; Fujita, M.; Morse, C. L.; Brouwer, C.; Hong, J. S.; Pike, V. W.; Zoghbi, S. S.; Innis, R. B.; Theodore, W. H. Neuroinflammation in temporal lobe epilepsy measured using positron emission tomographic imaging of translocator protein. JAMA Neurol. 2015, 72, 882, DOI: 10.1001/jamaneurol.2015.0941[Crossref], [PubMed], [CAS], Google Scholar407https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbhtFakuw%253D%253D&md5=cf61eb88e7a1a36486962814822ceb8dNeuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator ProteinGershen Leah D; Liow Jeih-San; Kreisl William C; Jenko Kimberly J; Fujita Masahiro; Morse Cheryl L; Brouwer Chad; Hong Jinsoo S; Pike Victor W; Zoghbi Sami S; Innis Robert B; Zanotti-Fregonara Paolo; Dustin Irene H; Inati Sara K; Theodore William H; Hirvonen JussiJAMA neurology (2015), 72 (8), 882-8 ISSN:.IMPORTANCE: Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([11C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES: To determine whether patients with TLE have widespread TSPO overexpression using [11C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [11C]PBR28 and another TSPO radioligand, [11C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS: In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [11C]PBR28, and 8 patients and 7 controls were scanned with [11C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURES: The [11C]PBR28 distribution volume (VT) corrected for free fraction (fP) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [11C]PBR28 and [11C]DPA-713 standardized uptake values from temporal regions. RESULTS: The [11C]PBR28 VT to fp ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%-42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%-32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [11C]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [11C]PBR28 was increased significantly in thalamus. Relative [11C]PBR28 and [11C]DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([11C]PBR28: 2%-6%; [11C]DPA-713: 4%-9%). Asymmetry of [11C]DPA-713 was greater than that of [11C]PBR28 (F = 29.4; P = .001). CONCLUSIONS AND RELEVANCE: Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug-resistant epilepsy.408Kreisl, W. C.; Lyoo, C. H.; McGwier, M.; Snow, J.; Jenko, K. J.; Kimura, N.; Corona, W.; Morse, C. L.; Zoghbi, S. S.; Pike, V. W.; McMahon, F. J.; Turner, R. S.; Innis, R. B. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain 2013, 136, 2228– 2238, DOI: 10.1093/brain/awt145[Crossref], [PubMed], [CAS], Google Scholar408https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sjjtlSgtA%253D%253D&md5=57cd580cdbeacbec216c5c5bcc1b5748In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's diseaseKreisl William C; Lyoo Chul Hyoung; McGwier Meghan; Snow Joseph; Jenko Kimberly J; Kimura Nobuyo; Corona Winston; Morse Cheryl L; Zoghbi Sami S; Pike Victor W; McMahon Francis J; Turner R Scott; Innis Robert BBrain : a journal of neurology (2013), 136 (Pt 7), 2228-38 ISSN:.Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.409Kreisl, W. C.; Fujita, M.; Fujimura, Y.; Kimura, N.; Jenko, K. J.; Kannan, P.; Hong, J.; Morse, C. L.; Zoghbi, S. S.; Gladding, R. L.; Jacobson, S.; Oh, U.; Pike, V. W.; Innis, R. B. Comparison of [11C]-(R)-PK 11195 and [11C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: Implications for positron emission tomographic imaging of this inflammation biomarker. NeuroImage 2010, 49, 2924– 2932, DOI: 10.1016/j.neuroimage.2009.11.056[Crossref], [PubMed], [CAS], Google Scholar409https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktlSkt7k%253D&md5=6ee406da710253d3b27ca9a494089f1eComparison of [11C]-(R)-PK 11195 and [11C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarkerKreisl, William C.; Fujita, Masahiro; Fujimura, Yota; Kimura, Nobuyo; Jenko, Kimberly J.; Kannan, Pavitra; Hong, Jinsoo; Morse, Cheryl L.; Zoghbi, Sami S.; Gladding, Robert L.; Jacobson, Steven; Oh, Unsong; Pike, Victor W.; Innis, Robert B.NeuroImage (2010), 49 (4), 2924-2932CODEN: NEIMEF; ISSN:1053-8119. (Elsevier B.V.)Ten percent of humans lack specific binding of [11C]PBR28 to 18 kDa translocator protein (TSPO), a biomarker for inflammation. "Non-binders" have not been reported using another TSPO radioligand, [11C]-(R)-PK 11195, despite its use for more than two decades. This study asked two questions: (1) What is the cause of non-binding to PBR28 and (2) Why has this phenomenon not been reported using [11C]-(R)-PK 11195. Methods: Five binders and five non-binders received whole-body imaging with both [11C]-(R)-PK 11195 and [11C]PBR28. In vitro binding was performed using leukocyte membranes from binders and non-binders and the tritiated versions of the ligand. Rhesus monkeys were imaged with [11C]-(R)-PK 11195 at baseline and after blockade of TSPOs. Results: Using [11C]PBR28, uptake in all five organs with high densities of TSPO (lung, heart, brain, kidney, and spleen) was 50% to 75% lower in non-binders than in binders. In contrast, [11C]-(R)-PK 11195 distinguished binders and non-binders in only heart and lung. For the in vitro assay, [3H]PBR28 had more than 10-fold lower affinity to TSPO in non-binders than in binders. The in vivo specific binding of [11C]-(R)-PK 11195 in monkey brain was ∼80-fold lower than that reported for [11C]PBR28. Conclusions: Based on binding of [3H] PK 11195 to leukocyte membranes, both binders and non-binders express TSPO. Non-binding to PBR28 is caused by its low affinity for TSPO in non-binders. Non-binding may be differentially expressed in organs of the body. The relatively low in vivo specific binding of [11C]-(R)-PK 11195 may have obscured its detection of non-binding in peripheral organs.410Kobayashi, M.; Jiang, T.; Telu, S.; Zoghbi, S. S.; Gunn, R. N.; Rabiner, E. A.; Owen, D. R.; Guo, Q.; Pike, V. W.; Innis, R. B.; Fujita, M. 11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195. J. Cereb. Blood Flow Metab. 2018, 38, 393– 403, DOI: 10.1177/0271678X17699223[Crossref], [PubMed], [CAS], Google Scholar410https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFOhtL0%253D&md5=d6bd9f42f469b96c3da8a7f79c77ad1311C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195Kobayashi, Masato; Jiang, Teresa; Telu, Sanjay; Zoghbi, Sami S.; Gunn, Roger N.; Rabiner, Eugenii A.; Owen, David R.; Guo, Qi; Pike, Victor W.; Innis, Robert B.; Fujita, MasahiroJournal of Cerebral Blood Flow & Metabolism (2018), 38 (3), 393-403CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)Positron emission tomog. (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent 11C-(R)-PK11195 in human imaging. This study sought to quant. measure the "signal to background" ratio (assessed as binding potential (BPND)) of 11C-(R)-PK11195 compared to one of the most promising second-generation radioligands, 11C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either 11C-(R)-PK11195 (16 subjects) or 11C-DPA-713 (22 subjects). To measure the amt. of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30-90 mg PO). 11C-DPA-713 showed a significant sensitivity to genotype in brain, whereas 11C-(R)-PK11195 did not. Lassen occupancy plot anal. revealed that the specific binding of 11C-DPA-713 was much greater than that of 11C-(R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for 11C-DPA-713 (7.3) than for 11C-(R)-PK11195 (0.75). Although the high specific binding of 11C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution vol. increased over time, consistent with the accumulation of radiometabolites in brain.411Cagnin, A.; Brooks, D. J.; Kennedy, A. M.; Gunn, R. N.; Myers, R.; Turkheimer, F. E.; Jones, T.; Banati, R. B. In-vivo measurement of activated microglia in dementia. Lancet 2001, 358, 461– 467, DOI: 10.1016/S0140-6736(01)05625-2[Crossref], [PubMed], [CAS], Google Scholar411https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MvmvVWjsw%253D%253D&md5=3574a5e3502039300c6f45a1403b57d7In-vivo measurement of activated microglia in dementiaCagnin A; Brooks D J; Kennedy A M; Gunn R N; Myers R; Turkheimer F E; Jones T; Banati R BLancet (London, England) (2001), 358 (9280), 461-7 ISSN:0140-6736.BACKGROUND: Activated microglia have a key role in the brain's immune response to neuronal degeneration. The transition of microglia from the normal resting state to the activated state is associated with an increased expression of receptors known as peripheral benzodiazepine binding sites, which are abundant on cells of mononuclear phagocyte lineage. We used brain imaging to study expression of these sites in healthy individuals and patients with Alzheimer's disease. METHODS: We studied 15 normal individuals (age 32-80 years), eight patients with Alzheimer's disease, and one patient with minimal cognitive impairment. Quantitative in-vivo measurements of glial activation were obtained with positron emission tomography (PET) and carbon-11-labelled (R)-PK11195, a specific ligand for the peripheral benzodiazepine binding site. FINDINGS: In normal individuals, regional [11C](R)-PK11195 binding did not significantly change with age, except in the thalamus, where an age-dependent increase was found. By contrast, patients with Alzheimer's disease showed significantly increased regional [11C](R)-PK11195 binding in the entorhinal, temporoparietal, and cingulate cortex. INTERPRETATION: In-vivo detection of increased [11C](R)-PK11195 binding in Alzheimer-type dementia, including mild and early forms, suggests that microglial activation is an early event in the pathogenesis of the disease.412Calsolaro, V.; Edison, P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimer's Dementia 2016, 12, 719– 732, DOI: 10.1016/j.jalz.2016.02.010[Crossref], [PubMed], [CAS], Google Scholar412https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28bpvVyhtg%253D%253D&md5=455f22ccbc7a16b20131d4d834935205Neuroinflammation in Alzheimer's disease: Current evidence and future directionsCalsolaro Valeria; Edison PaulAlzheimer's & dementia : the journal of the Alzheimer's Association (2016), 12 (6), 719-32 ISSN:.Several attempts have been made to treat Alzheimer's disease (AD) using anti-amyloid strategies with disappointing results. It is clear that the "amyloid cascade hypothesis" alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies. Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful. In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression. We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro-inflammatory factors, and neuronal damage. We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target.413Fan, Z.; Okello, A. A.; Brooks, D. J.; Edison, P. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease. Brain 2015, 138, 3685– 3698, DOI: 10.1093/brain/awv288[Crossref], [PubMed], [CAS], Google Scholar413https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zmsVSisQ%253D%253D&md5=42ef5ce0e01faabc925eaf1ed4b50673Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer's diseaseFan Zhen; Okello Aren A; Edison Paul; Brooks David JBrain : a journal of neurology (2015), 138 (Pt 12), 3685-98 ISSN:.Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer's disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer's disease. A group of eight patients with a diagnosis of Alzheimer's disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer's disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimer's disease process with associated synaptic dysfunction and reduced glucose metabolism. Voxel-wise correlation analysis suggests that neuroinflammation is associated with localized amyloid deposition and glucose metabolism over time, however, the level of inflammation could also occur independently of amyloid pathology, especially in the later stages of Alzheimer's disease.414Fan, Z.; Brooks, D. J.; Okello, A.; Edison, P. An early and late peak in microglial activation in Alzheimer’s disease trajectory. Brain 2017, 140, 792– 803, DOI: 10.1093/brain/aww349[Crossref], [PubMed], [CAS], Google Scholar414https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c7pt1yjsg%253D%253D&md5=42aba449a7fb9e714b63e0a9d952c1d5An early and late peak in microglial activation in Alzheimer's disease trajectoryFan Zhen; Brooks David J; Okello Aren; Edison Paul; Brooks David JBrain : a journal of neurology (2017), 140 (3), 792-803 ISSN:.Amyloid-β deposition, neuroinflammation and tau tangle formation all play a significant role in Alzheimer's disease. We hypothesized that there is microglial activation early on in Alzheimer's disease trajectory, where in the initial phase, microglia may be trying to repair the damage, while later on in the disease these microglia could be ineffective and produce proinflammatory cytokines leading to progressive neuronal damage. In this longitudinal study, we have evaluated the temporal profile of microglial activation and its relationship between fibrillar amyloid load at baseline and follow-up in subjects with mild cognitive impairment, and this was compared with subjects with Alzheimer's disease. Thirty subjects (eight mild cognitive impairment, eight Alzheimer's disease and 14 controls) aged between 54 and 77 years underwent 11C-(R)PK11195, 11C-PIB positron emission tomography and magnetic resonance imaging scans. Patients were followed-up after 14 ± 4 months. Region of interest and Statistical Parametric Mapping analysis were used to determine longitudinal alterations. Single subject analysis was performed to evaluate the individualized pathological changes over time. Correlations between levels of microglial activation and amyloid deposition at a voxel level were assessed using Biological Parametric Mapping. We demonstrated that both baseline and follow-up microglial activation in the mild cognitive impairment cohort compared to controls were increased by 41% and 21%, respectively. There was a longitudinal reduction of 18% in microglial activation in mild cognitive impairment cohort over 14 months, which was associated with a mild elevation in fibrillar amyloid load. Cortical clusters of microglial activation and amyloid deposition spatially overlapped in the subjects with mild cognitive impairment. Baseline microglial activation was increased by 36% in Alzheimer's disease subjects compared with controls. Longitudinally, Alzheimer's disease subjects showed an increase in microglial activation. In conclusion, this is one of the first longitudinal positron emission tomography studies evaluating longitudinal changes in microglial activation in mild cognitive impairment and Alzheimer's disease subjects. We found there is an initial longitudinal reduction in microglial activation in subjects with mild cognitive impairment, while subjects with Alzheimer's disease showed an increase in microglial activation. This could reflect that activated microglia in mild cognitive impairment initially may adopt a protective activation phenotype, which later change to a cidal pro-inflammatory phenotype as disease progresses and amyloid clearance fails. Thus, we speculate that there might be two peaks of microglial activation in the Alzheimer's disease trajectory; an early protective peak and a later pro-inflammatory peak. If so, anti-microglial agents targeting the pro-inflammatory phenotype would be most beneficial in the later stages of the disease.415Kreisl, W. C.; Lyoo, C. H.; Liow, J.-S.; Wei, M.; Snow, J.; Page, E.; Jenko, K. J.; Morse, C. L.; Zoghbi, S. S.; Pike, V. W.; Turner, R. S.; Innis, R. B. 11C-PBR28 binding to translocator protein increases with progression of Alzheimer’s disease. Neurobiol. Aging 2016, 44, 53– 61, DOI: 10.1016/j.neurobiolaging.2016.04.011[Crossref], [PubMed], [CAS], Google Scholar415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnslGmu7c%253D&md5=c7994f40cd6985e7253015ed5c6a9cae11C-PBR28 binding to translocator protein increases with progression of Alzheimer's diseaseKreisl, William C.; Lyoo, Chul Hyoung; Liow, Jeih-San; Wei, Monica; Snow, Joseph; Page, Emily; Jenko, Kimberly J.; Morse, Cheryl L.; Zoghbi, Sami S.; Pike, Victor W.; Turner, R. Scott; Innis, Robert B.Neurobiology of Aging (2016), 44 (), 53-61CODEN: NEAGDO; ISSN:0197-4580. (Elsevier)This longitudinal study sought to det. whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomog. imaging with the TSPO radioligand 11C-PBR28 was performed at baseline and after a median follow-up of 2.7 years in 14 amyloid-pos. patients and 8 amyloid-neg. controls. Patients had a greater increase in TSPO binding than controls in inferior parietal lobule, precuneus, occipital cortex, hippocampus, entorhinal cortex, and combined middle and inferior temporal cortex. TSPO binding in temporoparietal regions increased from 3.9% to 6.3% per annum in patients, but ranged from -0.5% to 1% per annum in controls. The change in TSPO binding correlated with cognitive worsening on clin. dementia rating scale-sum of boxes and reduced cortical vol. The annual rate of increased TSPO binding in temporoparietal regions was about 5-fold higher in patients with clin. progression (n = 9) compared with those who did not progress (n = 5). TSPO may serve as a biomarker of Alzheimer's progression and response to anti-inflammatory therapies.416Maeda, J.; Zhang, M.-R.; Okauchi, T.; Ji, B.; Ono, M.; Hattori, S.; Kumata, K.; Iwata, N.; Saido, T. C.; Trojanowski, J. Q.; Lee, V. M.-Y.; Staufenbiel, M.; Tomiyama, T.; Mori, H.; Fukumura, T.; Suhara, T.; Higuchi, M. In vivo positron emission tomographic imaging of glial responses to amyloid- and tau pathologies in mouse models of Alzheimer’s disease and related disorders. J. Neurosci. 2011, 31, 4720– 4730, DOI: 10.1523/JNEUROSCI.3076-10.2011[Crossref], [PubMed], [CAS], Google Scholar416https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVKrtbk%253D&md5=d3c03f77c86cb83aef2a8c46a0283713In vivo positron emission tomographic imaging of glial responses to amyloid-β and tau pathologies in mouse models of Alzheimer's disease and related disordersMaeda, Jun; Zhang, Ming-Rong; Okauchi, Takashi; Ji, Bin; Ono, Maiko; Hattori, Satoko; Kumata, Katsushi; Iwata, Nobuhisa; Saido, Takaomi C.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Staufenbiel, Matthias; Tomiyama, Takami; Mori, Hiroshi; Fukumura, Toshimitsu; Suhara, Tetsuya; Higuchi, MakotoJournal of Neuroscience (2011), 31 (12), 4720-4730CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-pos. microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-pos. tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomog. (PET) with 2 classes of TSPO radioligands, [11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was obsd. in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11C]Pittsburgh Compd.-B, to plaques. In these animals, [11C]AC-5216 yielded better TSPO contrasts than [18F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an addnl. line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. These data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.417Teodoro, R.; Moldovan, R.-P.; Lueg, C.; Günther, R.; Donat, C. K.; Ludwig, F.-A.; Fischer, S.; Deuther-Conrad, W.; Wünsch, B.; Brust, P. Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptors. Org. Med. Chem. Lett. 2013, 3, 11, DOI: 10.1186/2191-2858-3-11[Crossref], [PubMed], [CAS], Google Scholar417https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1Cqt7fM&md5=d04cb162a16c55d06d2639be02a8a282Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptorsTeodoro, Rodrigo; Moldovan, Rares-Petru; Lueg, Corinna; Guenther, Robert; Donat, Cornelius K.; Ludwig, Friedrich-Alexander; Fischer, Steffen; Deuther-Conrad, Winnie; Wuensch, Bernhard; Brust, PeterOrganic and Medicinal Chemistry Letters (2013), 3 (1), 11, 18 pp.CODEN: OMCLBC; ISSN:2191-2858. (Springer GmbH)Background: The level of expression of cannabinoid receptor type 2 (CB2R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB2R in the brain. Positron emission tomog. (PET) is an imaging technique, which allows quant. monitoring of very low amts. of radiolabeled compds. in living organisms at high temporal and spatial resoln. and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination of N-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biol. evaluation of the potential of the two tracers [18F]1 and [18F]2 as CB2 receptor PET imaging agents. Results: High binding affinity and specificity towards CB2 receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliph. and arom. fluorine in the selected labeling sites of 1 and 2. Aliph. and arom. radiofluorinations were optimized, and [18F]1 and [18F]2 were achieved in radiochem. yields of ≥30% with radiochem. purities of ≥98% and specific activities of 250 to 450 GBq/μmol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood-brain barrier (BBB) but undergo strong peripheral metab. At 30 min after injection, unmetabolized [18F]1 and [18F]2 accounted for 60% and 2% as well as 66% and 80% of the total activity in the plasma and brain, resp. The main radiometabolite of [18F]2 could be identified as the free acid [18F]10, which has no affinity towards the CB1 and CB2 receptors but can cross the BBB. Conclusions: N-aryl-oxadiazolyl-propionamides can successfully be radiolabeled with 18F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB2R. Despite a promising in vitro behavior, a rather rapid peripheral metab. of [18F]1 and [18F]2 in mice and the generation of brain permeable radiometabolites hamper the application of these radiotracers in vivo. However, it is expected that future synthetic modification aiming at a replacement of metabolically susceptible structural elements of [18F]1 and [18F]2 will help to elucidate the potential of this class of compds. for CB2R PET studies.418Zimmer, E.; Leuzy, A.; Benedet, A.; Breitner, J.; Gauthier, S.; Rosa-Neto, P. Tracking Neuroinflammation in Alzheimer’s Disease: The role of positron emission tomography imaging. J. Neuroinflammation 2014, 11, 120, DOI: 10.1186/1742-2094-11-120[Crossref], [PubMed], [CAS], Google Scholar418https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVCitrzJ&md5=99bc071c92e3e50cfdcee7860aa5179fTracking neuroinflammation in Alzheimer's disease: the role of positron emission tomography imagingZimmer, Eduardo Rigon; Leuzy, Antoine; Benedet, Andrea Lessa; Breitner, John; Gauthier, Serge; Rosa-Neto, PedroJournal of Neuroinflammation (2014), 11 (), 120/1-120/12CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)A review. Alzheimer's disease (AD) has been reconceptualized as a dynamic pathophysiol. process, where the accumulation of amyloid-beta (Aβ) is thought to trigger a cascade of neurodegenerative events resulting in cognitive impairment and, eventually, dementia. In addn. to Aβ pathol., various lines of research have implicated neuroinflammation as an important participant in AD pathophysiol. Currently, neuroinflammation can be measured in vivo using positron emission tomog. (PET) with ligands targeting diverse biol. processes such as microglial activation, reactive astrocytes and phospholipase A2 activity. In terms of therapeutic strategies, despite a strong rationale and epidemiol. studies suggesting that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the prevalence of AD, clin. trials conducted to date have proven inconclusive. In this respect, it has been hypothesized that NSAIDs may only prove protective if administered early on in the disease course, prior to the accumulation of significant AD pathol. In order to test various hypotheses pertaining to the exact role of neuroinflammation in AD, studies in asymptomatic carriers of mutations deterministic for early-onset familial AD may prove of use. In this respect, PET ligands for neuroinflammation may act as surrogate markers of disease progression, allowing for the development of more integrative models of AD, as well as for the measuring of target engagement in the context of clin. trials using NSAIDs. In this review, we address the biol. basis of neuroinflammatory changes in AD, underscore therapeutic strategies using anti-inflammatory compds., and shed light on the possibility of tracking neuroinflammation in vivo using PET imaging ligands.419Moldovan, R.-P.; Hausmann, K.; Deuther-Conrad, W.; Brust, P. Development of highly affine and selective fluorinated cannabinoid type 2 receptor ligands. ACS Med. Chem. Lett. 2017, 8, 566– 571, DOI: 10.1021/acsmedchemlett.7b00129[ACS Full Text], [CAS], Google Scholar419https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmslKrtrw%253D&md5=1c8da7e06fb35ae367e71a94fa08f49cDevelopment of Highly Affine and Selective Fluorinated Cannabinoid Type 2 Receptor LigandsMoldovan, Rares-Petru; Hausmann, Kristin; Deuther-Conrad, Winnie; Brust, PeterACS Medicinal Chemistry Letters (2017), 8 (5), 566-571CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Cannabinoid type 2 receptors (CB2 receptors) are involved in various pathol. processes, and the visualization of their in vivo availability with positron emission tomog. (PET) is of high interest. The study focuses on the introduction of fluorine into the structure of the highly affine and selective CB2 receptor ligand N-(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (5). A novel series of compds. was developed by modifying (i) the adamantane-3-position, (ii) the imidazole-N-Ph ring, and (iii) the imidazole-2-position, and the impact on the CB2 binding affinity and selectivity toward cannabinoid type 1 receptors (CB1) was evaluated. This study identified compd. 15 as one of the most potent (Ki(CB2) = 0.29 nM) and selective (CB1/CB2 > 10000) CB2 receptor ligands discovered so far, eligible for the development of an 18F-labeled PET radiotracer.420Chen, M.-K.; Guilarte, T. R. Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair. Pharmacol. Ther. 2008, 118, 1– 17, DOI: 10.1016/j.pharmthera.2007.12.004[Crossref], [PubMed], [CAS], Google Scholar420https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlvVSqsb0%253D&md5=19a49bb0a99b1b167bdd8b63ca61c5d2Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repairChen, Ming-Kai; Guilarte, Tomas R.Pharmacology & Therapeutics (2008), 118 (1), 1-17CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review. For over 15 years, the peripheral benzodiazepine receptor (PBR), recently named translocator protein 18 kDa (TSPO) has been studied as a biomarker of reactive gliosis and inflammation assocd. with a variety of neuropathol. conditions. Early studies documented that in the brain parenchyma, TSPO is exclusively localized in glial cells. Under normal physiol. conditions, TSPO levels are low in the brain neuropil but they markedly increase at sites of brain injury and inflammation making it uniquely suited for assessing active gliosis. This research has generated significant efforts from multiple research groups throughout the world to apply TSPO as a marker of "active" brain pathol. using in vivo imaging modalities such as Positron Emission Tomog. (PET) in exptl. animals and humans. Further, in the last few years, there has been an increased interest in understanding the mol. and cellular function(s) of TSPO in glial cells. The latest evidence suggests that TSPO may not only serve as a biomarker of active brain disease but also the use of TSPO-specific ligands may have therapeutic implications in brain injury and repair. This review presents an overview of the history and function of TSPO focusing on studies related to its use as a sensor of active brain disease in exptl. animals and in human studies.421Hirvonen, J.; Kreisl, W. C.; Fujita, M.; Dustin, I.; Khan, O.; Appel, S.; Zhang, Y.; Morse, C.; Pike, V. W.; Innis, R. B.; Theodore, W. H. Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy. J. Nucl. Med. 2012, 53, 234– 240, DOI: 10.2967/jnumed.111.091694[Crossref], [PubMed], [CAS], Google Scholar421https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjsVSltLo%253D&md5=ef475e7c8d24ea63d83345fabdc5b120Increased in vivo expression of an inflammatory marker in temporal lobe epilepsyHirvonen, Jussi; Kreisl, William C.; Fujita, Masahiro; Dustin, Irene; Khan, Omar; Appel, Shmuel; Zhang, Yi; Morse, Cheryl; Pike, Victor W.; Innis, Robert B.; Theodore, William H.Journal of Nuclear Medicine (2012), 53 (2), 234-240CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Animal studies and clin. observations suggest that epilepsy is assocd. with inflammation. Translocator protein (TSPO) (18 kDa), a marker of inflammation, is increased in vitro in surgical samples from patients with temporal lobe epilepsy. TSPO can be measured in the living human brain with PET and the novel radioligand 11C-PBR28. In this study, we sought to det. whether in vivo expression of TSPO is increased ipsilateral to the seizure focus in patients with temporal lobe epilepsy. Methods: Sixteen patients with unilateral temporal lobe epilepsy and 30 healthy subjects were studied with 11C-PBR28 PET and MRI. Uptake of radioactivity after injection of 11C-PBR28 was measured from regions of interest drawn bilaterally onto MR images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired-samples t test. Results: We found that brain uptake was higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without. Conclusion: We found increased uptake of radioactivity after injection of 11C-PBR28 ipsilateral to the seizure focus in patients with temporal lobe epilepsy, suggesting increased expression of TSPO. Studies in larger samples are required to confirm this finding and det. the clin. utility of imaging TSPO in temporal lobe epilepsy.422Boutin, H.; Chauveau, F.; Thominiaux, C.; Gregoire, M.-C.; James, M. L.; Trebossen, R.; Hantraye, P.; Dolle, F.; Tavitian, B.; Kassiou, M. 11C-DPA-713: A novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J. Nucl. Med. 2007, 48, 573– 581, DOI: 10.2967/jnumed.106.036764[Crossref], [PubMed], [CAS], Google Scholar422https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVert7nK&md5=55c934a5f699ff8890ecb90481b09a9211C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammationBoutin, Herve; Chauveau, Fabien; Thominiaux, Cyrille; Gregoire, Marie-Claude; James, Michelle L.; Trebossen, Regine; Hantraye, Philippe; Dolle, Frederic; Tavitian, Bertrand; Kassiou, MichaelJournal of Nuclear Medicine (2007), 48 (4), 573-581CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)The induction of neuroinflammatory processes, characterized by upregulation of the peripheral benzodiazepine receptor (PBR) expressed by microglial cells, is well correlated with neurodegenerative diseases and with acute neuronal loss. The continually increasing incidence of neurodegenerative diseases in developed countries has become a major health problem, for which the development of diagnostic and follow-up tools is required. Here we investigated a new PBR ligand suitable for PET to monitor neuroinflammatory processes as an indirect hallmark of neurodegeneration. We compared PK11195, the ref. compd. for PBR binding sites, with the new ligand DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), a PET scan was performed using 11C-PK11195 or 11C-DPA-713. Immunohistochem. for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD11) specific markers as well as 3H-PK11195 autoradiog. studies were then correlated with the imaging data. Seven days after a unilateral injection of AMPA in the striatum, 11C-DPA-713 exhibits a better contrast between healthy and damaged brain parenchyma than 11C-PK11195 (2.5-fold ± 0.14 increase vs. 1.6-fold ± 0.05 increase, resp.). 11C-DPA-713 and 11C-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, 11C-DPA-713 uptake was significantly lower than 11C-PK11195. Modeling of the data using the simplified ref. tissue model shows that the binding potential was significantly higher for 11C-DPA-713 than for 11C-PK11195. 11C-DPA-713 displays a higher signal-to-noise ratio than 11C-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of 11C-DPA-713. Although further studies in humans are required, 11C-DPA-713 represents a suitable alternative to 11C-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.423Chaney, A. M.; Johnson, E. M.; Cropper, H. C.; James, M. L. PET imaging of neuroinflammation using [11C]DPA-713 in a mouse model of ischemic stroke. J. Visualized Exp. 2018, 136, 57243, DOI: 10.3791/57243424Butler, T.; Ichise, M.; Teich, A. F.; Gerard, E.; Osborne, J.; French, J.; Devinsky, O.; Kuzniecky, R.; Gilliam, F.; Pervez, F.; Provenzano, F.; Goldsmith, S.; Vallabhajosula, S.; Stern, E.; Silbersweig, D. Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. Journal of Neuroimaging. 2013, 23, 129– 131, DOI: 10.1111/j.1552-6569.2010.00572.x[Crossref], [PubMed], [CAS], Google Scholar424https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38zjsFSltA%253D%253D&md5=da9523048f08c0c471976b158b6d1514Imaging inflammation in a patient with epilepsy due to focal cortical dysplasiaButler Tracy; Ichise Masanori; Teich Andrew F; Gerard Elizabeth; Osborne Joseph; French Jacqueline; Devinsky Orrin; Kuzniecky Ruben; Gilliam Frank; Pervez Fahad; Provenzano Frank; Goldsmith Stanley; Vallabhajosula Shankar; Stern Emily; Silbersweig DavidJournal of neuroimaging : official journal of the American Society of Neuroimaging (2013), 23 (1), 129-31 ISSN:.BACKGROUND AND PURPOSE: Evidence from animal models and examination of human epilepsy surgery specimens indicates that inflammation plays an important role in epilepsy. Positron emission tomography (PET) using [C11]PK11195, a marker of activated microglia, provides a means to visualize neuroinflammation in vivo in humans. We hypothesize that in patients with active epilepsy, [C11]PK11195 PET (PK-PET) may be able to identify areas of focally increased inflammation corresponding to the seizure onset zone. METHODS: A young woman with intractable epilepsy underwent PK-PET as part of an approved research study. PK-PET results were compared with results from other clinical studies. RESULTS: PK-PET revealed an area of focally increased radiotracer uptake in the right frontal lobe corresponding to this patient's seizure focus as identified by ictal and interictal 18F-fluorodeoxyglucose (FDG)-PET and EEG. Routine brain magnetic resonance imaging (MRI) was initially considered normal, though high-resolution studies showed possible subtle dysplasia of the right frontal lobe. The patient underwent a right frontal lobe resection, and pathological evaluation showed focal cortical dysplasia with activated microglia. CONCLUSIONS: PK-PET can identify neuroinflammation associated with subtle focal cortical dysplasia, and may therefore have a clinical role in guiding epilepsy surgery for patients with difficult-to-localize seizure foci.425Banati, R. B.; Goerres, G. W.; Myers, R.; Gunn, R. N.; Turkheimer, F. E.; Kreutzberg, G. W.; Brooks, D. J.; Jones, T.; Duncan, J. S. [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis. Neurology 1999, 53, 2199– 2199, DOI: 10.1212/WNL.53.9.2199[Crossref], [PubMed], [CAS], Google Scholar425https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252Fms1OqsA%253D%253D&md5=94ef58d64e1233fbd601561731b5529b11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitisBanati R B; Goerres G W; Myers R; Gunn R N; Turkheimer F E; Kreutzberg G W; Brooks D J; Jones T; Duncan J SNeurology (1999), 53 (9), 2199-203 ISSN:0028-3878.This study was designed to explore the feasibility of PET using [11C](R)-PK11195 as an in vivo marker of activated microglia/brain macrophages for the assessment of neuroinflammation in Rasmussen's encephalitis (RE). [11C](R)-PK11195 PET was carried out in four normal subjects, two patients with histologically confirmed RE, and three patients with clinically stable hippocampal sclerosis and low seizure frequency. Binding potential maps showing specific binding of [11C](R)-PK11195 were generated for each subject. Regional binding potential values were calculated for anatomically defined regions of interest after coregistration to and spatial transformation into the subjects' own MRI. In one patient with RE who underwent hemispherectomy, the resected, paraffin-embedded brain tissue was stained with an antibody (CR3/43) that labels activated human microglia. Whereas specific binding of [11C](R)-PK11195 in clinically stable hippocampal sclerosis was similar to that in normal brain, patients with RE showed a focal and diffuse increase in binding throughout the affected hemisphere. In RE, [11C](R)-PK11195 PET can reveal in vivo the characteristic, unilateral pattern known from postmortem neuropathologic study. PET imaging of activated microglia/brain macrophages offers a tool for investigation of a range of brain diseases where neuroinflammation is a component and in which conventional MRI does not unequivocally indicate an inflammatory tissue reaction. [11C](R)-PK11195 PET may help in the choice of appropriate biopsy sites and, further, may allow assessment of the efficacy of antiinflammatory disease-modifying treatment.426Gerhard, A.; Trender-Gerhard, I.; Turkheimer, F.; Quinn, N. P.; Bhatia, K. P.; Brooks, D. J. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov. Disord. 2006, 21, 89– 93, DOI: 10.1002/mds.20668[Crossref], [PubMed], [CAS], Google Scholar426https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28%252FjtlOkug%253D%253D&md5=43a010a5833feacfb848bbc8690b48ffIn vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsyGerhard Alexander; Trender-Gerhard Iris; Turkheimer Federico; Quinn Niall P; Bhatia Kailash P; Brooks David JMovement disorders : official journal of the Movement Disorder Society (2006), 21 (1), 89-93 ISSN:0885-3185.Progressive supranuclear palsy (PSP) is a neurodegenerative disease presenting with voluntary gaze difficulties, early falls, and Parkinsonism. Neuronal loss, associated with intracellular neurofibrillary tangles and activated microglia, is found targeting the basal ganglia, brainstem nuclei, and frontal cortex. [11C](R)-PK11195 PET is a marker of peripheral benzodiazepine binding sites (PBBS) expressed by activated microglia. We have used [11C](R)-PK11195 PET to demonstrate in vivo the degree and distribution of the glial response to the degenerative process in four patients with PSP. Compared to normal age-matched controls, the PSP patient group showed significantly increased mean [11C](R)-PK11195 binding in the basal ganglia, midbrain, the frontal lobe, and the cerebellum. Two of the patients were rescanned after 6 to 10 months and during that time the level of microglial activation remained stable. [11C](R)-PK11195 PET reveals a pattern of increased microglial activation in PSP patients involving cortical and subcortical regions that corresponds well with the known distribution of neuropathological changes. [11C](R)-PK11195 PET, therefore, may help in characterizing in vivo the underlying disease activity in PSP.427Passamonti, L.; Rodríguez, P. V.; Hong, Y. T.; Allinson, K. S. J.; Bevan-Jones, W. R.; Williamson, D.; Jones, P. S.; Arnold, R.; Borchert, R. J.; Surendranathan, A.; Mak, E.; Su, L.; Fryer, T. D.; Aigbirhio, F. I.; O’Brien, J. T.; Rowe, J. B. [11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy. Neurology 2018, 90, e1989 DOI: 10.1212/WNL.0000000000005610[Crossref], [PubMed], [CAS], Google Scholar427https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVags7zO&md5=b03709a8cfd65805b105bfb6921ff103[11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsyPassamonti, Luca; Rodriguez, Patricia Vazquez; Hong, Young T.; Allinson, Kieren S. J.; Bevan-Jones, W. Richard; Williamson, David; Jones, P. Simon; Arnold, Robert; Borchert, Robin J.; Surendranathan, Ajenthan; Mak, Elijah; Su, Li; Fryer, Tim D.; Aigbirhio, Franklin I.; O'Brien, John T.; Rowe, James B.Neurology (2018), 90 (22), e1989-e1996CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: We tested whether in vivo neuroinflammation relates to the distinctive distributions of pathol. in Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Methods: Sixteen patients with symptomatic AD (including amnestic mild cognitive impairment with amyloid-pos. PET scan), 16 patients with PSP-Richardson syndrome, and 13 age-, sex-, and education-matched healthy controls were included in this case-control study. Participants underwent [C]PK11195 PET scanning, which was used as an in vivo index of neuroinflammation. Results: [C]PK11195 binding in the medial temporal lobe and occipital, temporal, and parietal cortices was increased in patients with AD, relative both to patients with PSP and to controls. Compared to controls, patients with PSP showed elevated [C]PK11195 binding in the thalamus, putamen, and pallidum. [C]PK11195 binding in the cuneus/precuneus correlated with episodic memory impairment in AD, while [C]PK11195 binding in the pallidum, midbrain, and pons correlated with disease severity in PSP. Conclusions: Together, our results suggest that neuroinflammation has an important pathogenic role in the 2 very different human neurodegenerative disorders of AD and PSP. The increase and distribution of microglial activation suggest that immunotherapeutic strategies may be useful in slowing the progression of both diseases.428Cagnin, A.; Rossor, M.; Sampson, E. L.; MacKinnon, T.; Banati, R. B. In vivo detection of microglial activation in frontotemporal dementia. Ann. Neurol. 2004, 56, 894– 897, DOI: 10.1002/ana.20332[Crossref], [PubMed], [CAS], Google Scholar428https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2crpsFKmtA%253D%253D&md5=8794eeac45992a918676d776faa582c1In vivo detection of microglial activation in frontotemporal dementiaCagnin Annachiara; Rossor Martin; Sampson Elizabeth L; Mackinnon Toby; Banati Richard BAnnals of neurology (2004), 56 (6), 894-7 ISSN:0364-5134.Using positron emission tomography and [(11)C](R)-PK11195, a marker of "peripheral benzodiazepine sites" that is upregulated on activated microglia during progressive tissue pathology, we show increased binding of [(11)C](R)-PK11195 in frontotemporal lobar degeneration in the typically affected frontotemporal brain regions. This implies the presence of an active glial response reflecting progressive neuronal degeneration. It also suggests that increased [(11)C](R)-PK11195 binding, previously demonstrated for Alzheimer's disease, may occur independently from increased amyloid plaque formation, given that it is not a characteristic feature of frontotemporal lobar degeneration.429Kim, M.-J.; McGwier, M.; Jenko, K. J.; Snow, J.; Morse, C.; Zoghbi, S. S.; Pike, V. W.; Innis, R. B.; Kreisl, W. C. Neuroinflammation in frontotemporal lobar degeneration revealed by 11C-PBR28 PET. Ann. Clin. Transl. Neurol. 2019, 6, 1327– 1331, DOI: 10.1002/acn3.50802[Crossref], [PubMed], [CAS], Google Scholar429https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVertr3J&md5=119fc55f76058b39b14657ca9dc154c4Neuroinflammation in frontotemporal lobar degeneration revealed by 11C-PBR28 PETKim, Min-Jeong; McGwier, Meghan; Jenko, Kimberly J.; Snow, Joseph; Morse, Cheryl; Zoghbi, Sami S.; Pike, Victor W.; Innis, Robert B.; Kreisl, William C.Annals of Clinical and Translational Neurology (2019), 6 (7), 1327-1331CODEN: ACTNCG; ISSN:2328-9503. (John Wiley & Sons, Inc.)This study used 11C-PBR28 positron emission tomog. (PET) imaging to det. whether levels of 18-kDa translocator protein (TSPO), an inflammation-specific biomarker, are increased in frontotemporal lobar degeneration (FTLD) patients. 11C-PBR28, 18F-FDG, and 11C-PIB brain PET scans, as well as magnetic resonance imaging (MRI), were conducted in four FTLD patients and 22 healthy controls. 11C-PBR28 scans revealed that all FTLD patients showed increased TSPO binding vs. controls. Significantly greater increases in TSPO were obsd. in the frontal, lateral temporal, parietal, and occipital cortices, topog. consistent with individual clin. phenotypes and with brain MRI and 18F-FDG PET. Amyloid burden was not increased.430Hammoud, D. A.; Endres, C. J.; Chander, A. R.; Guilarte, T. R.; Wong, D. F.; Sacktor, N. C.; McArthur, J. C.; Pomper, M. G. Imaging glial cell activation with [11C]- R -PK11195 in patients with AIDS. J. NeuroVirol. 2005, 11, 346– 355, DOI: 10.1080/13550280500187351[Crossref], [PubMed], [CAS], Google Scholar430https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVWitLjJ&md5=476b5e302b64e4bebae9797146d5c883Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDSHammoud, Dima A.; Endres, Christopher J.; Chander, Ankit R.; Guilarte, Tomas R.; Wong, Dean F.; Sacktor, Ned C.; McArthur, Justin C.; Pomper, Martin G.Journal of NeuroVirology (2005), 11 (4), 346-355CODEN: JNVIFK; ISSN:1355-0284. (Taylor & Francis, Inc.)Glial cell activation occurs in response to brain injury and is present in a wide variety of inflammatory processes including dementia assocd. with human immunodeficiency virus (HIV). HIV-infected glial cells release cytokines and chemokines that, along with viral neurotoxins, contribute to neuronal damage and apoptosis. The purpose of this study was to det. if glial cell activation in HIV-pos. (HIV+) patients could be detected noninvasively, in vivo, using [11C]-R-PK11195 with positron emission tomog. (PET). [11C]-R-PK11195 is a selective radioligand for the peripheral benzodiazepine receptor (PBR), and is known to reflect the extent of glial cell activation. A subaim was to det. if nondemented HIV+ patients could be distinguished from those with HIV-assocd. dementia (HAD) on the basis of [11C]-R-PK11195 binding. Five healthy volunteers and 10 HIV+ patients underwent PET with [11C]-R-PK11195. Time-radioactivity curves (TACs) were generated from dynamic PET images in nine regions of interest (ROIs) drawn on coregistered magnetic resonance imaging (MRI) scans. The av. radioactivity was calcd. in each ROI and was normalized to the av. radioactivity in white matter. Patients with HAD showed significantly higher [11C]-R-PK11195 binding than controls in five out of eight brain regions. Nondemented HIV+ patients did not show significantly increased binding compared to controls. HIV+ patients overall (demented and nondemented) showed significantly higher radioligand binding than controls in five brain regions. Patients with HAD did not show significant differences in binding when compared to HIV+ nondemented patients. The findings of this pilot study support a role for glial cell activation in HAD, and that PET with [11C]-R-PK11195 can detect the concomitants of neuronal damage in individuals infected with HIV.431Coughlin, J. M.; Wang, Y.; Ma, S.; Yue, C.; Kim, P. K.; Adams, A. V.; Roosa, H. V.; Gage, K. L.; Stathis, M.; Rais, R.; Rojas, C.; McGlothan, J. L.; Watkins, C. C.; Sacktor, N.; Guilarte, T. R.; Zhou, Y.; Sawa, A.; Slusher, B. S.; Caffo, B.; Kassiou, M.; Endres, C. J.; Pomper, M. G. Regional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIV. J. NeuroVirol. 2014, 20, 219– 232, DOI: 10.1007/s13365-014-0239-5[Crossref], [PubMed], [CAS], Google Scholar431https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptVCksr4%253D&md5=3434731fbfcd7d4335294395be863daaRegional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIVCoughlin, Jennifer M.; Wang, Yuchuan; Ma, Shuangchao; Yue, Chen; Kim, Pearl K.; Adams, Ashley V.; Roosa, Heidi V.; Gage, Kenneth L.; Stathis, Marigo; Rais, Rana; Rojas, Camilo; McGlothan, Jennifer L.; Watkins, Crystal C.; Sacktor, Ned; Guilarte, Tomas R.; Zhou, Yun; Sawa, Akira; Slusher, Barbara S.; Caffo, Brian; Kassiou, Michael; Endres, Christopher J.; Pomper, Martin G.Journal of NeuroVirology (2014), 20 (3), 219-232CODEN: JNVIFK; ISSN:1355-0284. (Springer)Imaging the brain distribution of translocator protein (TSPO), a putative biomarker for glial cell activation and neuroinflammation, may inform management of individuals infected with HIV by uncovering regional abnormalities related to neurocognitive deficits and enable non-invasive therapeutic monitoring. Using the second-generation TSPO-targeted radiotracer, [11C]DPA-713, we conducted a positron emission tomog. (PET) study to compare the brains of 12 healthy human subjects to those of 23 individuals with HIV who were effectively treated with combination antiretroviral therapy (cART). Compared to PET data from age-matched healthy control subjects, [11C]DPA-713 PET of individuals infected with HIV demonstrated significantly higher vol.-of-distribution (VT) ratios in white matter, cingulate cortex, and supramarginal gyrus, relative to overall gray matter VT, suggesting localized glial cell activation in susceptible regions. Regional TSPO abnormalities were evident within a sub-cohort of neuro-asymptomatic HIV subjects, and an increase in the VT ratio within frontal cortex was specifically linked to individuals affected with HIV-assocd. dementia. These findings were enabled by employing a gray matter normalization approach for PET data quantification, which improved test-retest reproducibility, intra-class correlation within the healthy control cohort, and sensitivity of uncovering abnormal regional findings.432Vera, J. H.; Guo, Q.; Cole, J. H.; Boasso, A.; Greathead, L.; Kelleher, P.; Rabiner, E. A.; Kalk, N.; Bishop, C.; Gunn, R. N.; Matthews, P. M.; Winston, A. Neuroinflammation in treated HIV-positive individuals: A TSPO PET study. Neurology 2016, 86, 1425– 1432, DOI: 10.1212/WNL.0000000000002485[Crossref], [PubMed], [CAS], Google Scholar432https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xmt1aqsLw%253D&md5=e86a6b61cceffee711e1ed1e808afdb4Neuroinflammation in treated HIV-positive individuals: A TSPO PET studyVera, Jaime H.; Guo, Qi; Cole, James H.; Boasso, Adriano; Greathead, Louise; Kelleher, Peter; Rabiner, Eugenii A.; Kalk, Nicola; Bishop, Courtney; Gunn, Roger N.; Matthews, Paul M.; Winston, AlanNeurology (2016), 86 (15), 1425-1432CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: To explore the effects of microglial activation on brain function and structure, and its relationship with peripheral inflammatory markers, in treated, HIV-pos. individuals, using in vivo [C]PBR28 PET (to measure the 18 kDa translocator protein [TSPO]). Methods: Cognitively healthy HIV-pos. individuals on suppressive antiretroviral therapy and HIV-neg. individuals (controls) underwent brain [C]PBR28 PET and MRI. HIV-pos. patients completed neuropsychol. testing and CSF testing for chemokines. The concn. of bacterial ribosomal 16sDNA in plasma was measured as a marker of microbial translocation. Results: HIV-pos. individuals showed global increases in TSPO expression compared to controls (cor. p < 0.01), with significant regional increases in the parietal (p = 0.001) and occipital (p = 0.046) lobes and in the globus pallidus (p = 0.035). TSPO binding in the hippocampus, amygdala, and thalamus were assocd. with poorer global cognitive performance in tasks assessing verbal and visual memory (p < 0.05). Increased TSPO binding was assocd. with increased brain white matter diffusion MRI mean diffusivity in HIV-pos. individuals, a lower CD4/CD8 ratio, and both high pretreatment HIV RNA and plasma concn. ribosomal 16s DNA (p < 0.05). Conclusions: Cognitively healthy HIV-pos. individuals show evidence for a chronically activated brain innate immune response and elevated blood markers of microbial translocation despite effective control of plasma viremia. Increased brain inflammation is assocd. with poorer cognitive performance and white matter microstructural pathol., suggesting a possible role in cognitive impairments found in some HIV-pos. patients despite effective treatment.433Kreisl, W. C.; Mbeo, G.; Fujita, M.; Zoghbi, S. S.; Pike, V. W.; Innis, R. B.; McArthur, J. C. Stroke incidentally identified using improved positron emission tomography for microglial activation. Arch. Neurol. 2009, 66, 1288– 1289, DOI: 10.1001/archneurol.2009.208[Crossref], [PubMed], [CAS], Google Scholar433https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnosF2mtg%253D%253D&md5=316336ae3ec1963c083f61a7054c25ceStroke incidentally identified using improved positron emission tomography for microglial activationKreisl William C; Mbeo Gilbert; Fujita Masahiro; Zoghbi Sami S; Pike Victor W; Innis Robert B; McArthur Justin CArchives of neurology (2009), 66 (10), 1288-9 ISSN:.There is no expanded citation for this reference.434Abid, K. A.; Sobowale, O. A.; Parkes, L. M.; Naish, J.; Parker, G. J. M.; du Plessis, D.; Brough, D.; Barrington, J.; Allan, S. M.; Hinz, R.; Parry-Jones, A. R. Assessing inflammation in acute intracerebral hemorrhage with PK11195 PET and dynamic contrast-enhanced MRI. J. Neuroimaging. 2018, 28, 158– 161, DOI: 10.1111/jon.12477[Crossref], [PubMed], [CAS], Google Scholar434https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7jvFSntQ%253D%253D&md5=337b65a99958337c01ab5e8741d6d015Assessing Inflammation in Acute Intracerebral Hemorrhage with PK11195 PET and Dynamic Contrast-Enhanced MRIAbid Kamran A; Sobowale Oluwaseun A; Parkes Laura M; Naish Josephine; Parker Geoff J M; Brough David; Barrington Jack; Allan Stuart M; Hinz Rainer; Parry-Jones Adrian R; Abid Kamran A; Sobowale Oluwaseun A; du Plessis Daniel; Parry-Jones Adrian R; Parker Geoff J MJournal of neuroimaging : official journal of the American Society of Neuroimaging (2018), 28 (2), 158-161 ISSN:.BACKGROUND AND PURPOSE: Studies in animal models suggest that inflammation is a major contributor to secondary injury after intracerebral hemorrhage (ICH). Direct, noninvasive monitoring of inflammation in the human brain after ICH will facilitate early-phase development of anti-inflammatory treatments. We sought to investigate the feasibility of multimodality brain imaging in subacute ICH. METHODS: Acute ICH patients were recruited to undergo multiparametric MRI (including dynamic contrast-enhanced measurement of blood-brain barrier transfer constant (K(trans) ) and PET with [(11) C]-(R)-PK11195). [(11) C]-(R)-PK11195 binds to the translocator protein 18 kDa (TSPO), which is rapidly upregulated in activated microglia. Circulating inflammatory markers were measured at the time of PET. RESULTS: Five patients were recruited to this feasibility study with imaging between 5 and 16 days after onset. Etiologies included hypertension-related small vessel disease, cerebral amyloid angiopathy (CAA), cavernoma, and arteriovenous malformation (AVM). [(11) C]-(R)-PK11195 binding was low in all hematomas and 2 (patient 2 [probable CAA] and 4 [AVM]) cases showed widespread increase in binding in the perihematomal region versus contralateral. All had increased K(trans) in the perihematomal region (mean difference = 2.2 × 10(-3) minute(-1) ; SD = 1.6 × 10(-3) minute(-1) ) versus contralateral. Two cases (patients 1 [cavernoma] and 4 [AVM]) had delayed surgery (3 and 12 months post-onset, respectively) with biopsies showing intense microglial activation in perilesional tissue. CONCLUSIONS: Our study demonstrates for the first time the feasibility of performing complex multimodality brain imaging for noninvasive monitoring of neuroinflammation for this severe stroke subtype.435Turner, M. R.; Cagnin, A.; Turkheimer, F. E.; Miller, C. C. J.; Shaw, C. E.; Brooks, D. J.; Leigh, P. N.; Banati, R. B. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: An [11C](R)-PK11195 positron emission tomography study. Neurobiol. Dis. 2004, 15, 601– 609, DOI: 10.1016/j.nbd.2003.12.012[Crossref], [PubMed], [CAS], Google Scholar435https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXivVKmsro%253D&md5=a30edf14a0c20ea64c78dc1330785aceEvidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography studyTurner, M. R.; Cagnin, A.; Turkheimer, F. E.; Miller, C. C. J.; Shaw, C. E.; Brooks, D. J.; Leigh, P. N.; Banati, R. B.Neurobiology of Disease (2004), 15 (3), 601-609CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Science)Microglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the "peripheral benzodiazepine binding site" expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [11C](R)-PK11195 PET of the brain. Vols. of interest were defined to obtain [11C](R)-PK11195 regional binding potential values for motor and "extra-motor" regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clin. (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathol. is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways.436Paganoni, S.; Alshikho, M. J.; Luppino, S.; Chan, J.; Pothier, L.; Schoenfeld, D.; Andres, P. L.; Babu, S.; Zürcher, N. R.; Loggia, M. L.; Barry, R. L.; Luotti, S.; Nardo, G.; Trolese, M. C.; Pantalone, S.; Bendotti, C.; Bonetto, V.; De Marchi, F.; Rosen, B.; Hooker, J.; Cudkowicz, M.; Atassi, N. A pilot trial of RNS60 in amyotrophic lateral sclerosis. Muscle Nerve 2019, 59, 303– 308, DOI: 10.1002/mus.26385[Crossref], [PubMed], [CAS], Google Scholar436https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtVOmsLY%253D&md5=93f8c116b3c40a6b36190ad48b6aaca9A pilot trial of RNS60 in amyotrophic lateral sclerosisPaganoni, Sabrina; Alshikho, Mohamad J.; Luppino, Sarah; Chan, James; Pothier, Lindsay; Schoenfeld, David; Andres, Patricia L.; Babu, Suma; Zuercher, Nicole R.; Loggia, Marco L.; Barry, Robert L.; Luotti, Silvia; Nardo, Giovanni; Trolese, Maria Chiara; Pantalone, Serena; Bendotti, Caterina; Bonetto, Valentina; De Marchi, Fabiola; Rosen, Bruce; Hooker, Jacob; Cudkowicz, Merit; Atassi, NazemMuscle & Nerve (2019), 59 (3), 303-308CODEN: MUNEDE; ISSN:0148-639X. (John Wiley & Sons, Inc.)RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclin. models. RNS60 is administered by weekly i.v. infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients. The planned treatment duration was 23 wk and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomog. (PET) imaging and plasma biomarkers of inflammation. Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 wk of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers. Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression.437Liang, S. H.; Chen, J. M.; Normandin, M. D.; Chang, J. S.; Chang, G. C.; Taylor, C. K.; Trapa, P.; Plummer, M. S.; Para, K. S.; Conn, E. L.; Lopresti-Morrow, L.; Lanyon, L. F.; Cook, J. M.; Richter, K. E. G.; Nolan, C. E.; Schachter, J. B.; Janat, F.; Che, Y.; Shanmugasundaram, V.; Lefker, B. A.; Enerson, B. E.; Livni, E.; Wang, L.; Guehl, N. J.; Patnaik, D.; Wagner, F. F.; Perlis, R.; Holson, E. B.; Haggarty, S. J.; El Fakhri, G.; Kurumbail, R. G.; Vasdev, N. Discovery of a highly selective glycogen synthase kinase-3 inhibitor (PF-04802367) that modulates tau phosphorylation in the brain: Translation for PET neuroimaging. Angew. Chem., Int. Ed. 2016, 55, 9601– 9605, DOI: 10.1002/anie.201603797[Crossref], [PubMed], [CAS], Google Scholar437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtV2itLbF&md5=83a1bfbe16022e6cc30445c2afbab0a1Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET NeuroimagingLiang, Steven H.; Chen, Jinshan Michael; Normandin, Marc D.; Chang, Jeanne S.; Chang, George C.; Taylor, Christine K.; Trapa, Patrick; Plummer, Mark S.; Para, Kimberly S.; Conn, Edward L.; Lopresti-Morrow, Lori; Lanyon, Lorraine F.; Cook, James M.; Richter, Karl E. G.; Nolan, Charlie E.; Schachter, Joel B.; Janat, Fouad; Che, Ye; Shanmugasundaram, Veerabahu; Lefker, Bruce A.; Enerson, Bradley E.; Livni, Elijahu; Wang, Lu; Guehl, Nicolas J.; Patnaik, Debasis; Wagner, Florence F.; Perlis, Roy; Holson, Edward B.; Haggarty, Stephen J.; El Fakhri, Georges; Kurumbail, Ravi G.; Vasdev, NeilAngewandte Chemie, International Edition (2016), 55 (33), 9601-9605CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncol., and neurol. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A 11C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.438Benito, C.; Tolón, R. M.; Pazos, M. R.; Núñez, E.; Castillo, A. I.; Romero, J. Cannabinoid CB2 receptors in human brain inflammation. Br. J. Pharmacol. 2008, 153, 277– 285, DOI: 10.1038/sj.bjp.0707505[Crossref], [PubMed], [CAS], Google Scholar438https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovFCktg%253D%253D&md5=acc7f2244e1db16d66e5953eadecb381Cannabinoid CB2 receptors in human brain inflammationBenito, C.; Tolon, R. M.; Pazos, M. R.; Nunez, E.; Castillo, A. I.; Romero, J.British Journal of Pharmacology (2008), 153 (2), 277-285CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)A review. The presence of functional cannabinoid CB2 receptors in the CNS has provoked considerable controversy over the past few years. Formerly considered as an exclusively peripheral receptor, it is now accepted that it is also present in limited amts. and distinct locations in the brain of several animal species, including humans. Furthermore, the inducible nature of these receptors under neuroinflammatory conditions, in contrast to CB1, makes them attractive targets for the development of novel therapeutic approaches. In fact, the undesired psychoactive effects caused by CB1 activation have largely limited the clin. use of cannabinoid-related compds. that act on these receptors. In this review some recent findings on the antiinflammatory properties of CB2 receptors are presented, as well as new perspectives that have been obtained based on studies of human postmortem brain samples. In addn., various working hypotheses are also proposed and discussed. British Journal of Pharmacol. (2008) 153, 277-285; doi:10.1038/sj.bjp.0707505; published online 15 Oct. 2007.439Benito, C.; Núñez, E.; Tolón, R. M.; Carrier, E. J.; Rábano, A.; Hillard, C. J.; Romero, J. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J. Neurosci. 2003, 23, 11136– 11141, DOI: 10.1523/JNEUROSCI.23-35-11136.2003[Crossref], [PubMed], [CAS], Google Scholar439https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvV2gtbw%253D&md5=c324980efac10a672fc425ef376694f1Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brainsBenito, Cristina; Nunez, Estefania; Tolon, Rosa M.; Carrier, Erica J.; Rabano, Alberto; Hillard, Cecilia J.; Romero, JulianJournal of Neuroscience (2003), 23 (35), 11136-11141CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)The endocannabinoid system is still poorly understood. Recently, the basic elements that constitute it, i.e., membrane receptors, endogenous ligands, and mechanisms for termination of the signaling process, have been partially characterized. There is a considerable lack of information, however, concerning the distribution, concn., and function of those components in the human body, particularly during pathol. events. We have studied the status of some of the components of the endocannabinoid system, fatty acid amide hydrolase and cannabinoid CB1 and CB2 receptors, in postmortem brains from patients with Alzheimer's disease. Using specific polyclonal antibodies, we have performed immunohistochem. anal. in hippocampus and entorhinal cortex sections from brains of Alzheimer's disease patients. Our results show that both fatty acid amide hydrolase and cannabinoid CB2 receptors are abundantly and selectively expressed in neuritic plaque-assocd. astrocytes and microglia, resp., whereas the expression of CB1 receptors remains unchanged. In addn., the hydrolase activity seems to be elevated in the plaques and surrounding areas. Thus, some elements of the endocannabinoid system may be postulated as possible modulators of the inflammatory response assocd. with this neurodegenerative process and as possible targets for new therapeutic approaches.440Ahamed, M.; van Veghel, D.; Ullmer, C.; Van Laere, K.; Verbruggen, A.; Bormans, G. M. Synthesis, biodistribution and in vitro evaluation of brain permeable high affinity type 2 cannabinoid receptor agonists [11C]MA2 and [18F]MA3. Front. Neurosci. 2016, 10, 431, DOI: 10.3389/fnins.2016.00431[Crossref], [PubMed], [CAS], Google Scholar440https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svnvFKktg%253D%253D&md5=3240509303d6d5aa35daa26c7e8a59fbSynthesis, Biodistribution and In vitro Evaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [(11)C]MA2 and [(18)F]MA3Ahamed Muneer; van Veghel Daisy; Verbruggen Alfons; Bormans Guy M; Ullmer Christoph; Van Laere KoenFrontiers in neuroscience (2016), 10 (), 431 ISSN:1662-4548.The type 2 cannabinoid receptor (CB2) is a member of the endocannabinoid system and is known for its important role in (neuro)inflammation. A PET-imaging agent that allows in vivo visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and in vitro evaluation of a carbon-11 ([(11)C]MA2) and a fluorine-18 ([(18)F]MA3) labeled analog of a highly potent N-arylamide oxadiazole CB2 agonist (EC50 = 0.015 nM). MA2 and MA3 behaved as potent CB2 agonist (EC50: 3 nM and 0.1 nM, respectively) and their in vitro binding affinity for hCB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group) was found to have higher binding affinity and EC50 values when compared to the originally reported trifluoromethyl analog 12. [(11)C]MA2 and [(18)F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [(11)C]MA2 and [(18)F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes for in vivo imaging of brain CB2 receptors. However, in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted.441Haider, A.; Spinelli, F.; Herde, A. M.; Mu, B.; Keller, C.; Margelisch, M.; Weber, M.; Schibli, R.; Mu, L.; Ametamey, S. M. Evaluation of 4-oxo-quinoline-based CB2 PET radioligands in R6/2 chorea Huntington mouse model and human ALS spinal cord tissue. Eur. J. Med. Chem. 2018, 145, 746– 759, DOI: 10.1016/j.ejmech.2017.12.097[Crossref], [PubMed], [CAS], Google Scholar441https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlOhsL0%253D&md5=12d0514c79a7a3e45b1aa751971af494Evaluation of 4-oxo-quinoline-based CB2 PET radioligands in R6/2 chorea huntington mouse model and human ALS spinal cord tissueHaider, Ahmed; Spinelli, Francesco; Herde, Adrienne Muller; Mu, Boshuai; Keller, Claudia; Margelisch, Markus; Weber, Markus; Schibli, Roger; Mu, Linjing; Ametamey, Simon M.European Journal of Medicinal Chemistry (2018), 145 (), 746-759CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)The cannabinoid receptor 2 (CB2) has been implicated in a series of neurodegenerative disorders and has emerged as an interesting biol. target for therapeutic as well as diagnostic purposes. In the present work, we describe an improved radiosynthetic approach to obtain the previously reported CB2-specific PET radioligand [18F]RS-126 in higher radiochem. yields and molar activities. Addnl., the study revealed that prolongation of the [18F]RS-126 fluoroalkyl side chain ultimately leads to an improved stability towards mouse liver enzymes but is accompanied by a redn. in selectivity over the cannabinoid receptor 1 (CB1). Huntington-related phenotypic changes as well as striatal D2R downregulation were confirmed for the transgenic R6/2 mouse model. CB2 upregulation in R6/2 Chorea Huntington mice was obsd. in hippocampus, cortex, striatum and cerebellum by qPCR, however, these results could not be confirmed at the protein level by PET imaging. Furthermore, we evaluated the utility of the newly developed [11C]RS-028, a potent [18F]RS-126 deriv. with increased polarity and high selectivity over CB1 in post-mortem human ALS spinal cord and control tissue. Applying in vitro autoradiog., the translational relevance of CB2 imaging was demonstrated by the specific binding of [11C]RS-028 to post-mortem human ALS spinal cord tissue.442Mu, L.; Bieri, D.; Slavik, R.; Drandarov, K.; Müller, A.; Cermak, S.; Weber, M.; Schibli, R.; Krämer, S. D.; Ametamey, S. M. Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor. J. Neurochem. 2013, 126, 616– 624, DOI: 10.1111/jnc.12354[Crossref], [PubMed], [CAS], Google Scholar442https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlSqu7zN&md5=863e2ab5064c38648f1618a9a2424410Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptorMu, Linjing; Bieri, Daniel; Slavik, Roger; Drandarov, Konstantin; Mueller, Adrienne; Cermak, Stjepko; Weber, Markus; Schibli, Roger; Kraemer, Stefanie D.; Ametamey, Simon M.Journal of Neurochemistry (2013), 126 (5&6), 616-624CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The cannabinoid type 2 (CB2) receptor plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease and is therefore a very promising target for therapeutic approaches as well as for imaging. Based on the literature, we identified one 4-oxoquinoline deriv. (designated KD2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB2. [11C]KD2 was obtained in 99% radiochem. purity. Moderate blood-brain barrier (BBB) passage was predicted for KD2 from an in vitro transport assay with P-glycoprotein-transfected Madin Darby canine kidney cells. No efflux of KD2 by P-glycoprotein was detected. In vitro autoradiog. of rat and mouse spleen slices demonstrated that [11C]KD2 exhibits high specific binding towards CB2. High spleen uptake of [11C]KD2 was obsd. in dynamic positron emission tomog. (PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB2 agonist, GW405833. A pilot autoradiog. study with post-mortem spinal cord slices from amyotrophic lateral sclerosis (ALS) patients with [11C]KD2 suggested the presence of CB2 receptors under disease conditions. Specificity of [11C]KD2 binding could also be demonstrated on these human tissues. In conclusion, [11C]KD2 shows good in vitro and in vivo properties as a potential PET tracer for CB2. The cannabinoid type 2 receptor (CB2) plays an important role in neuroinflammatory and neuro-degenerative diseases. [11C]KD2, a new CB2 radioligand, exhibits selectivity towards CB2 receptor in vitro and in vivo in rat. A pilot autoradiog. study with spinal cord slices from amyotrophic lateral sclerosis patients with [11C]KD2 suggested the presence of CB2 under disease conditions (Figure). Selective CB2 agonist, GW405833.443Puchałowicz, K.; Tarnowski, M.; Baranowska-Bosiacka, I.; Chlubek, D.; Dziedziejko, V. P2X and P2Y receptors—Role in the pathophysiology of the nervous system. Int. J. Mol. Sci. 2014, 15, 23672– 23704, DOI: 10.3390/ijms151223672[Crossref], [PubMed], [CAS], Google Scholar443https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsl2jug%253D%253D&md5=c6aa1b669c9167f2bacd16e99f995304P2X and P2Y receptors-role in the pathophysiology of the nervous systemPuchalowicz, Kamila; Tarnowski, Maciej; Baranowska-Bosiacka, Irena; Chlubek, Dariusz; Dziedziejko, ViolettaInternational Journal of Molecular Sciences (2014), 15 (12), 23672-23704, 33 pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Purinergic signalling plays a crucial role in proper functioning of the nervous system. Mechanisms depending on extracellular nucleotides and their P2 receptors also underlie a no. of nervous system dysfunctions. This review aims to present the role of purinergic signalling, with particular focus devoted to role of P2 family receptors, in epilepsy, depression, neuropathic pain, nervous system neoplasms, such as glioma and neuroblastoma, neurodegenerative diseases like Parkinson's disease, Alzheimer's disease and multiple sclerosis. The above-mentioned conditions are assocd. with changes in expression of extracellular ectonucleotidases, P2X and P2Y receptors in neurons and glial cells, as well as releasing considerable amts. of nucleotides from activated or damaged nervous tissue cells into the extracellular space, which contributes to disturbance in purinergic signalling. The numerous studies indicate a potential possibility of using synthetic agonists/antagonists of P2 receptors in treatment of selected nervous system diseases. This is of particular significance, since numerous available agents reveal a low effectiveness and often produce side effects.444Janssen, B.; Vugts, D. J.; Funke, U.; Spaans, A.; Schuit, R. C.; Kooijman, E.; Rongen, M.; Perk, L. R.; Lammertsma, A. A.; Windhorst, A. D. Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A-740003 as a novel tracer of neuroinflammation: Synthesis and initial preclinical evaluation of [11C]A-740003. J. Labelled Compd. Radiopharm. 2014, 57, 509– 516, DOI: 10.1002/jlcr.3206[Crossref], [PubMed], [CAS], Google Scholar444https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtV2ju7vI&md5=984ecb5c357bc4297576edb73a7d6b28Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A-740003 as a novel tracer of neuroinflammationJanssen, Bieneke; Vugts, Danielle J.; Funke, Uta; Spaans, Arnold; Schuit, Robert C.; Kooijman, Esther; Rongen, Marissa; Perk, Lars R.; Lammertsma, Adriaan A.; Windhorst, Albert D.Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (8), 509-516CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)Neuroinflammation, in particular activation of microglia, is thought to play an important role in the progression of neurodegenerative diseases. In activated microglia, the purinergic P2X7 receptor is upregulated. A-740003, a highly affine and selective P2X7 receptor antagonist, is a promising candidate for the development of a radiotracer for imaging of neuroinflammation by positron emission tomog. For this purpose, [11C]A-740003 was synthesized and evaluated in vivo with respect to both tracer metab. and biodistribution. In plasma, a moderate metabolic rate was seen. In healthy rat brain, only marginal uptake of [11C]A-740003 was obsd. and, therefore, metabolites in brain could not be detd. Whether the minimal brain uptake is due to the low expression levels of the P2X7 receptor in healthy brain or to limited transport across the blood-brain barrier has yet to be elucidated.445Ory, D.; Celen, S.; Gijsbers, R.; Van Den Haute, C.; Postnov, A.; Koole, M.; Vandeputte, C.; Andres, J.-I.; Alcazar, J.; De Angelis, M.; Langlois, X.; Bhattacharya, A.; Schmidt, M.; Letavic, M. A.; Vanduffel, W.; Van Laere, K.; Verbruggen, A.; Debyser, Z.; Bormans, G. Preclinical evaluation of a P2 × 7 receptor-selective radiotracer: PET studies in a rat model with local overexpression of the human P2 × 7 receptor and in nonhuman primates. J. Nucl. Med. 2016, 57, 1436– 1441, DOI: 10.2967/jnumed.115.169995[Crossref], [PubMed], [CAS], Google Scholar445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslaktLbF&md5=16eff3aaba96236308c909eaa79f154cPreclinical evaluation of a P2X7 receptor-selective radiotracer: PET studies in a rat model with local overexpression of the human P2X7 receptor and in nonhuman primatesOry, Dieter; Celen, Sofie; Gijsbers, Rik; Van Den Haute, Chris; Postnov, Andrey; Koole, Michel; Vandeputte, Caroline; Andres, Jose-Ignacio; Alcazar, Jesus; De Angelis, Meri; Langlois, Xavier; Bhattacharya, Anindya; Schmidt, Mark; Letavic, Michael A.; Vanduffel, Wim; Van Laere, Koen; Verbruggen, Alfons; Debyser, Zeger; Bormans, GuyJournal of Nuclear Medicine (2016), 57 (9), 1436-1441CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)The P2X7 receptor (P2X7R) orchestrates neuroinflammation, and this is the basis for an increased interest in the development of antagonists inhibiting P2X7R function in the brain. This study provides the preclin. evaluation of 11C-JNJ-54173717, a PET tracer for P2X7R in both rats and nonhuman primates. 11C-JNJ-54173717 is a high-affinity radiotracer for the human P2X7R (hP2X7R). Biodistribution and radiometabolite studies were performed. Viral vectors encoding either enhanced green fluorescent protein-hP2X7R or 3flag-hP2X7R were engineered and validated in cell culture. HP2X7R was regionally overexpressed in the rat striatum after stereotactic injection of viral vectors. Dynamic small-animal PET studies were performed in vector-injected rats and in healthy monkeys using 11C-JNJ-54173717. The affinity of JNJ-54173717 was 1.6 ± 0.1 nM in a rat cortex P2X7R membrane binding assay. In a functional assay at the recombinant human and rat P2X7R orthologs, the half maximal inhibitory concn. (IC50) of JNJ-54173717 was 4.2 ± 0.01 nM and 7.6 ± 0.01 nM, resp. The rat biodistribution study showed that 11C-JNJ-54173717 crossed the blood-brain barrier and was cleared from plasma mainly via the hepatobiliary pathway. A polar radiometabolite was found in rat plasma. No radiometabolites were detected in rat brain. Dynamic small-animal PET showed binding of 11C-JNJ-54173717 in the striatum expressing hP2X7R, with rapid washout from the noninjected control striatum and other brain regions. Likewise, 11C-JNJ-54173717 PET signal was blocked by a chem. distinct P2X7R ligand, indicating specific binding to P2X7R in the monkey brain. JNJ-54173717 is a high-affinity P2X7R antagonist. An animal rat model stably expressing hP2X7R was developed and validated, identifying favorable characteristics for 11C-JNJ-54173717 as a PET radioligand for in vivo visualization of hP2X7R. 11C-JNJ-54173717 selectively visualized P2X7R in the monkey brain, and this radioligand will be further evaluated in a clin. setting to study P2X7R expression levels in neurodegenerative disorders.446Janssen, B.; Vugts, D. J.; Molenaar, G. T. Synthesis og the first carbon-11 labelled P2Y12 receptor antagonist for imaging the anti-inflammatory phenotype of activated microglia. In 18th European Symposium on Radiopharmacy and Radiopharmaceuticals. Salzburg, Austria, EJNMMI Radiopharmacy and Chemistry; 2016; Vol. 1, p 10.447Van Weehaeghe, D.; Van Schoor, E.; De Vocht, J.; Koole, M.; Attili, B.; Celen, S.; Declercq, L.; Thal, D. R.; Van Damme, P.; Bormans, G.; Van Laere, K. TSPO versus P2 × 7 as a target for neuroinflammation: An in vitro and in vivo study. J. Nucl. Med. 2020, 61, 604– 607, DOI: 10.2967/jnumed.119.231985[Crossref], [PubMed], [CAS], Google Scholar447https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVOisLbE&md5=a35e3546525ae8e8e5115a385f1de054TSPO Versus P2X7 as a target for neuroinflammation: an in vitro and in vivo studyVan Weehaeghe, Donatienne; Van Schoor, Evelien; De Vocht, Joke; Koole, Michel; Attili, Bala; Celen, Sofie; Declercq, Lieven; Thal, Dietmar R.; Van Damme, Philip; Bormans, Guy; Van Laere, KoenJournal of Nuclear Medicine (2020), 61 (4), 604-607CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Neuroinflammation is important in amyotrophic lateral sclerosis (ALS). The P2X7 receptor (P2X7R) is a promising target for neuroinflammation. The objective of this study was to compare 18F-DPA714, a second-generation translocator protein tracer, with 11C-JNJ717, a novel P2X7R tracer, in vitro and in vivo in ALS. For the in vitro portion of the study, autoradiog. with 18F-DPA714 and 11C-JNJ717 was performed on human ALS brain sections in comparison to immunofluorescence with Iba1 and GFAP. For the in vivo portion, 3 male patients with early-stage ALS (59.3 ± 7.2 y old) and 6 healthy volunteers (48.2 ± 16.5 y old, 2 men and 4 women) underwent dynamic PET/MR scanning with 18F-DPA714 and 11C-JNJ717. Vol.-of-distribution images were calcd. using Logan plots and analyzed on a vol.-of-interest basis. Autoradiog. showed no difference in 11C-JNJ717 binding but did show increased 18F-DPA714 binding in the motor cortex correlating with Iba1 expression (glial cells). Similar findings were obsd. in vivo, with a 13% increase in 18F-DPA714 binding in the motor cortex. Conclusion: In symptomatic ALS patients, 18F-DPA714 showed increased signal whereas 11C-JNJ717 was not elevated.448Kawamura, K.; Maeda, J.; Hatori, A.; Okauchi, T.; Nagai, Y.; Higuchi, M.; Suhara, T.; Fukumura, T.; Zhang, M.-R. In vivo and in vitro imaging of I2 imidazoline receptors in the monkey brain. Synapse 2011, 65, 452– 455, DOI: 10.1002/syn.20897[Crossref], [PubMed], [CAS], Google Scholar448https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisF2hsbY%253D&md5=5c08dcfcc21875edc8c799cf584ff4d7In vivo and in vitro imaging of I2 imidazoline receptors in the monkey brainKawamura, Kazunori; Maeda, Jun; Hatori, Akiko; Okauchi, Takashi; Nagai, Yuji; Higuchi, Makoto; Suhara, Tetsuya; Fukumura, Toshimitsu; Zhang, Ming-RongSynapse (Hoboken, NJ, United States) (2011), 65 (5), 452-455CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)I2 imidazoline receptors (I2Rs) are assocd. with depression, Alzheimer's disease, and Huntington's disease. However, in vivo imaging of I2Rs in the monkey brain has not been reported until now. We performed in vitro and in vivo imaging of (I2Rs) in the monkey brain using 11C-labeled 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD) which has high and selective affinity of I2Rs. In an auto-radiog. (ARG) study, the distribution pattern of [11C]FTIMD in the monkey brain was similar to that of [3H]idazoxan binging to I2Rs in the human brain, which was previously described. The specific binding of [11C]FTIMD accounted for >97% of total binding in brain regions existing I2Rs. In positron emission tomog. (PET) studies, the radioactivity was accumulated in brain regions existing I2Rs ligand BU224, the accumulated radioactivity was decreased to approx. 66%-75% of the baseline measurement at 15-45 min after injection of [11C]FTIMD. These results suggest that [11C]FTIMD shows the specific-binging to I2Rs in the monkey brain as depicted by PET and ARG. We performed the first in vivo imaging of I2Rs using [11C]FTIMD in the monkey brain. Synapse, 2011. © 2010 Wiley-Liss, Inc.449Kawamura, K.; Naganawa, M.; Konno, F.; Yui, J.; Wakizaka, H.; Yamasaki, T.; Yanamoto, K.; Hatori, A.; Takei, M.; Yoshida, Y.; Sakaguchi, K.; Fukumura, T.; Kimura, Y.; Zhang, M.-R. Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4–11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). Nucl. Med. Biol. 2010, 37, 625– 635, DOI: 10.1016/j.nucmedbio.2010.02.013[Crossref], [PubMed], [CAS], Google Scholar449https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVOqu7c%253D&md5=c75ac9cfcffcafb1803c5f7bd9e865f9Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD)Kawamura, Kazunori; Naganawa, Mika; Konno, Fujiko; Yui, Joji; Wakizaka, Hidekatsu; Yamasaki, Tomoteru; Yanamoto, Kazuhiko; Hatori, Akiko; Takei, Makoto; Yoshida, Yuichiro; Sakaguchi, Kazuya; Fukumura, Toshimitsu; Kimura, Yuichi; Zhang, Ming-RongNuclear Medicine and Biology (2010), 37 (5), 625-635CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)Introduction: Imidazoline receptors (IRs) have been established as distinct receptors, and have been categorized into at least two subtypes (I1R and I2R). I2Rs are assocd. with depression, Alzheimer's disease, Huntington's disease and Parkinson's disease. A few positron emission tomog. (PET) probes for I2Rs have been synthesized, but a selective PET probe has not been evaluated for the imaging of I2Rs by PET. We labeled a selective I2R ligand 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole (FTIMD) with 11C and performed the first imaging of I2Rs by PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). Methods: [11C]FTIMD was prepd. by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11C]methyl iodide in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri(o-tol)phosphine. Biodistribution was investigated in rats by tissue dissection. [11C]FTIMD metabolites were measured in brain tissues and plasma. Dynamic PET scans were acquired in rats, and the kinetic parameters estd. Results: [11C]FTIMD was successfully synthesized with a suitable radioactivity for the injection. Co-injection with 0.1 mg/kg of cold FTIMD and BU224 induced a significant redn. in the brain-to-blood ratio 15 and 30 min after the injection. In metabolite anal., unchanged [11C]FTIMD in the brain was high (98%) 30 min after the injection. In PET studies, high radioactivity levels were obsd. in regions with a high d. of I2R. The radioactivity levels and V T values in the brain regions were prominently reduced by 1.0 mg/kg of BU224 pretreatment as compared with control. Conclusion: [11C]FTIMD showed specific binding to I2Rs in rat brains with a high d. of I2R.450Kealey, S.; Turner, E. M.; Husbands, S. M.; Salinas, C. A.; Jakobsen, S.; Tyacke, R. J.; Nutt, D. J.; Parker, C. A.; Gee, A. D. Imaging imidazoline-I2 binding sites in porcine brain using 11C-BU99008. J. Nucl. Med. 2013, 54, 139– 144, DOI: 10.2967/jnumed.112.108258[Crossref], [PubMed], [CAS], Google Scholar450https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFGjtLk%253D&md5=68e67a8c76efead745862846b6fe3037Imaging imidazoline-I2 binding sites in porcine brain using 11C-BU99008Kealey, Steven; Turner, Emma M.; Husbands, Stephen M.; Salinas, Cristian A.; Jakobsen, Steen; Tyacke, Robin J.; Nutt, David J.; Parker, Christine A.; Gee, Antony D.Journal of Nuclear Medicine (2013), 54 (1), 139-144CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)Changes in the d. of imidazofine-I2 binding sites have been obsd. in a range of neurol. disorders including Alzheimer's disease, Huntington's chorea, and glial tumor; however, the precise function of these sites remains unclear. A PET probe for I2 binding sites would further our understanding of the target and may find application as a biomarker for early disease diagnosis. Compd. BU99008 has previously been identified as a promising I2 ligand from autoradiog. studies, displaying high affinity and good selectivity toward the target. In this study, BU99008 was radiolabeled with 11C in order to image the I2 binding sites in vivo using PET. Methods: 11C-BU99008 was radiolabeled by N-alkylation of the desmethyl precursor using 11C-Me iodide. A series of PET expts. was performed to investigate the binding of 11C-BU99008 in porcine brains, in the presence or absence of a nonradiolabeled, competing I2 ligand, BU224. Results: 11C-BU99008 was obtained in good yield and specific activity. In vivo, 11C-BU99008 displayed good brain penetration and gave a heterogeneous distribution with high uptake in the thalamus and low uptake in the cortex and cerebellum. 11C-BU99008 brain kinetics were well described by the 1-tissue-compartment model, which was used to provide ests. for the total vol. of distribution (VT) across brain regions of interest. Baseline VT values were ranked in the following order: thalamus > striatum > hippocampus > frontal cortex ≥ cerebellum, consistent with the known distribution and concn. of I2 binding sites. Administration of a selective I2 binding site ligand, BU224, reduced the VT to near-homogeneous levels in all brain regions. Conclusion: 11C-BU99008 appears to be a suitable PET radioligand for imaging the I2 binding sites in vivo.451Parker, C. A.; Nabulsi, N.; Holden, D.; Lin, S. -f.; Cass, T.; Labaree, D.; Kealey, S.; Gee, A. D.; Husbands, S. M.; Quelch, D.; Carson, R. E.; Nutt, D. J.; Huang, Y.; Tyacke, R. J. Evaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding sites in rhesus brain. J. Nucl. Med. 2014, 55, 838– 844, DOI: 10.2967/jnumed.113.131854[Crossref], [PubMed], [CAS], Google Scholar451https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1CrsL0%253D&md5=28a20fa3406a91bd6d8d63edea29106aEvaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding sites in rhesus brainParker, Christine A.; Nabulsi, Nabeel; Holden, Daniel; Lin, Shu-fei; Cass, Tara; Labaree, David; Kealey, Steven; Gee, Antony D.; Husbands, Stephen M.; Quelch, Darren; Carson, Richard E.; Nutt, David J.; Huang, Yiyun; Tyacke, Robin J.Journal of Nuclear Medicine (2014), 55 (5), 838-844CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)The development of a PET radioligand selective for I2-imidazoline binding sites (I2BS) would enable, for the first time, specific, measurable in vivo imaging of this target protein, along with assessment of alterations in expression patterns of this protein in disease pathophysiol. Methods: BU99008 was identified as the most promising I2BS radioligand candidate and radiolabeled with 11C via methylation. The in vivo binding properties of 11C-BU99008 were assessed in rhesus monkeys to det. brain penetration, brain distribution, binding specificity and selectivity (via the use of the unlabeled blockers), and the most appropriate kinetic mode) for analyzing data generated with this PET radioligand. Results: 11C-BU99008 was demonstrated to readily enter the brain, resulting in a heterogeneous distribution (globus pallidus > cortical regions > cerebellum) consistent with the reported regional I2BS densities as detd. by human tissue section autoradiog. and preclin. in vivo PET studies in the pig. In vivo competition studies revealed that 11C-BU99008 displayed reversible kinetics specific for the I2BS. The multilinear anal. (MA1) model was the most appropriate anal. method for this PET radioligand in this species. The selective I2BS blocker BU224 was shown to cause a saturable, dose-dependent decrease in 11C-BU99008 binding in all regions of the brain assessed, further demonstrating the heterogeneous distribution of I2BS protein in the rhesus brain and binding specificity for this radioligand. Conclusion: These data demonstrate that 11C-BU99008 represents a specific and selective PET radioligand for imaging and quantifying the I2BS, in vivo, in the rhesus monkey. Further work is under way to translate the use of 11C-BU99008 to the clinic.452Tyacke, R. J.; Myers, J. F. M.; Venkataraman, A.; Mick, I.; Turton, S.; Passchier, J.; Husbands, S. M.; Rabiner, E. A.; Gunn, R. N.; Murphy, P. S.; Parker, C. A.; Nutt, D. J. Evaluation of 11 C-BU99008, a PET ligand for the imidazoline2 binding site in human brain. J. Nucl. Med. 2018, 59, 1597– 1602, DOI: 10.2967/jnumed.118.208009[Crossref], [PubMed], [CAS], Google Scholar452https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXktVajtrY%253D&md5=49ef228fd095cac95ce9d8edc1d10339Evaluation of 11C-BU99008, a PET ligand for the Imidazoline2 binding site in human brainTyacke, Robin J.; Myers, Jim F. M.; Venkataraman, Ashwin; Mick, Inge; Turton, Samuel; Passchier, Jan; Husbands, Stephen M.; Rabiner, Eugenii A.; Gunn, Roger N.; Murphy, Philip S.; Parker, Christine A.; Nutt, David J.Journal of Nuclear Medicine (2018), 59 (10), 1597-1602CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)The imidazoline2 binding site (I2BS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C-BU99008 has previously been identified as a putative PET radioligand. Here, we present the first in vivo characterization of this PET radioligand in humans and assess its test-retest reproducibility. Methods: Fourteen healthy male volunteers underwent dynamic PET imaging with 11C-BU99008 and arterial sampling. Six subjects were used in a test-retest assessment, and 8 were used in a pharmacol. evaluation, undergoing a second or third heterologous competition scan with the mixed I2BS/α2-adrenoceptor drug idazoxan (n = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid (n = 4; 50 mg). Regional time-activity data were generated from arterial plasma input functions cor. for metabolites using the most appropriate model to derive the outcome measure VT (regional distribution vol.). All image processing and kinetic analyses were performed in MIAKAT. Results: Brain uptake of 11C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment model was preferred. VT ests. were high in the striatum (105 ± 21 mL·cm-3), medium in the cingulate cortex (62 ± 10 mL·cm-3), and low in the cerebellum (41 ± 7 mL·cm-3). Test-retest reliability was reasonable. The uptake was dose-dependently reduced throughout the brain by pretreatment with idazoxan, with an av. block across all regions of about 60% (VT, ∼30 mL·cm-3) at the highest dose (80 mg). The median ED for idazoxan was 28 mg. Uptake was not blocked by pretreatment with the monoamine oxidase inhibitor isocarboxazid. Conclusion: 11C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I2BS distribution, and good test-retest reliability.453Ekblom, J.; Jossan, S. S.; Oreland, L.; Walum, E.; Aquilonius, S.-M. Reactive Gliosis and Monoamine Oxidase B. In Amine Oxidases: Function and Dysfunction; Tipton, K. F., Youdim, M. B. H., Barwell, C. J., Callingham, B. A., Lyles, G. A., Eds.; Springer: Vienna, Austria, 1994; pp 253– 258.454Schöll, M.; Carter, S. F.; Westman, E.; Rodriguez-Vieitez, E.; Almkvist, O.; Thordardottir, S.; Wall, A.; Graff, C.; Långström, B.; Nordberg, A. Early astrocytosis in autosomal dominant Alzheimer’s disease measured in vivo by multi-tracer positron emission tomography. Sci. Rep. 2015, 5, 16404, DOI: 10.1038/srep16404[Crossref], [PubMed], [CAS], Google Scholar454https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vgslCiug%253D%253D&md5=a61729478e88053544d07d38c2769f23Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomographyScholl Michael; Carter Stephen F; Rodriguez-Vieitez Elena; Almkvist Ove; Nordberg Agneta; Scholl Michael; Carter Stephen F; Westman Eric; Almkvist Ove; Thordardottir Steinunn; Graff Caroline; Nordberg Agneta; Almkvist Ove; Thordardottir Steinunn; Graff Caroline; Wall Anders; Langstrom BengtScientific reports (2015), 5 (), 16404 ISSN:.Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround β-amyloid (Aβ) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar Aβ, astrocytosis and cerebral glucose metabolism with the radiotracers (11)C-Pittsburgh compound-B (PIB), (11)C-deuterium-L-deprenyl (DED) and (18)F-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar Aβ or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.455Johansson, A.; Engler, H.; Blomquist, G.; Scott, B.; Wall, A.; Aquilonius, S.-M.; Långström, B.; Askmark, H. Evidence for astrocytosis in ALS demonstrated by [11C](l)-deprenyl-D2 PET. J. Neurol. Sci. 2007, 255, 17– 22, DOI: 10.1016/j.jns.2007.01.057[Crossref], [PubMed], [CAS], Google Scholar455https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVCjsrs%253D&md5=f9a033414237a4f0fe28eeed94557a04Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PETJohansson, Anders; Engler, Henry; Blomquist, Gunnar; Scott, Berit; Wall, Anders; Aquilonius, Sten-Magnus; Langstroem, Bengt; Askmark, HakanJournal of the Neurological Sciences (2007), 255 (1-2), 17-22CODEN: JNSCAG; ISSN:0022-510X. (Elsevier B.V.)To use deuterium-substituted [11C](L)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). In human brain, the enzyme MAO-B is primarily located in astrocytes. L-deprenyl binds to MAO-B and autoradiog. with 3H-L-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](L)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. Deuterium-substituted [11C](L)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. Increased uptake rate of [11C](L)-deprenyl was demonstrated in ALS in pons and white matter. This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](L)-deprenyl PET though further studies are needed to det. whether deuterium-substituted [11C](L)-deprenyl binding tracks disease progression and reflects astrocytosis.456Saura, J.; Bleuel, Z.; Ulrich, J.; Mendelowitsch, A.; Chen, K.; Shih, J. C.; Malherbe, P.; Da Prada, M.; Richards, J. G. Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistry. Neuroscience 1996, 70, 755– 774, DOI: 10.1016/S0306-4522(96)83013-2[Crossref], [PubMed], [CAS], Google Scholar456https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XivVKqsA%253D%253D&md5=b3a387bf13c2c99466a6ff85bdfa6993Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistrySaura, J.; Bleuel, Z.; Ulrich, J.; Mendelowitsch, A.; Chen, K.; Shih, J. C.; Malherbe, P.; Da Prada, M.; Richards, J. G.Neuroscience (Oxford) (1996), 70 (3), 755-74CODEN: NRSCDN; ISSN:0306-4522. (Elsevier)Monoamine oxidases (MAOs) are key enzymes in the metab. of amine neurotransmitters and neuromodulators and are targets for drug therapy in depression and Parkinson's and Alzheimer's diseases. Knowledge of their distribution in the brain is essential to understand their physiol. role. To study the regional distribution and abundance of MOA A and B in human brain, pituitary, and superior cervical ganglion, the authors used quant. enzyme radioautog. with radioligands, [3H]Ro41-1049 and [3H]lazabemide, resp. Furthermore, 35S-labeled oligonucleotides complementary to isoenzyme A and B mRNAs were used to map the cellular location of the resp. transcripts in adjacent sections by in situ hybridization histochem. A markedly different pattern of distribution of the isoenzymes was obsd. The highest levels of MAO A were measured in the superior cervical ganglion, locus coeruleus, interpeduncular nucleus, and ventromedial hypothalamic nucleus. The corresponding mRNA was detected only in the noradrenergic neurons of the superior cervical ganglion and locus coeruleus. In contrast to rat brain, MAO B was much more abundant in most human brain regions investigated. The highest levels were measured in the ependyma of ventricles, stria terminalis, and in individual hypothalamic neurons. MAO B transcripts were detected in serotoninergic raphe neurons, histaminergic hypothalamic neurons, and in dentate gyrus granule cells of the hippocampal formation. It was concluded that [3H]Ro41-1049 and [3H]lazabemide are extremely useful radioligands for high-resoln. analyses of the abundance and distribution of catalytic sites of MAO A and B, resp., in human brain sections. From the levels of mRNA detected, the cellular sites of synthesis of the isoenzymes are the noradrenergic neurons of the locus coeruleus (for MAO A) and the serotoninergic and histaminergic neurons of the raphe and posterior hypothalamus, resp. (for MAO B). The combination of quant. enzyme radioautog. with in situ hybridization histochem. is a useful approach to study, with high resoln., both the physiol. and pathophysiol. of MAOs in human brain.457Shukuri, M.; Takashima-Hirano, M.; Tokuda, K.; Takashima, T.; Matsumura, K.; Inoue, O.; Doi, H.; Suzuki, M.; Watanabe, Y.; Onoe, H. In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester. J. Nucl. Med. 2011, 52, 1094– 1101, DOI: 10.2967/jnumed.110.084046[Crossref], [PubMed], [CAS], Google Scholar457https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnltFGjsQ%253D%253D&md5=6721bba55894842b0f919f4cbf035ee8In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl esterShukuri Miho; Takashima-Hirano Misato; Tokuda Keiko; Takashima Tadayuki; Matsumura Kiyoshi; Inoue Osamu; Doi Hisashi; Suzuki Masaaki; Watanabe Yasuyoshi; Onoe HirotakaJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2011), 52 (7), 1094-101 ISSN:.UNLABELLED: Cyclooxygenase (COX)-1 and -2 are prostanoid-synthesizing enzymes that play important roles in the regulation of neuroinflammation and in the development of neurodegenerative disorders. However, the specific functions of these isoforms are still unclear. We recently developed (11)C-labeled ketoprofen methyl ester as a PET probe that targets the COXs for imaging neuroinflammation, though its responsible isoform is yet to be determined. In the present study, we performed ex vivo and in vivo imaging studies with (11)C-ketoprofen methyl ester and determined the contributions of the COX isoforms during the neuroinflammatory process. METHODS: To identify the COX isoform responsible for (11)C-ketoprofen methyl ester in the brain, we examined the ex vivo autoradiography of (11)C-ketoprofen methyl ester using COX-deficient mice. Time-dependent changes in accumulation of (11)C-ketoprofen methyl ester during the neuroinflammatory process were evaluated by PET in rats with hemispheric neuroinflammation induced by intrastriatal injection of lipopolysaccharide or quinolinic acid. In both rat models, cell-type specificity of COX isoform expression during neuroinflammation was identified immunohistochemically. RESULTS: Ex vivo autoradiographic analysis of COX-deficient mice revealed a significant reduction of (11)C-ketoprofen methyl ester accumulation only in COX-1-deficient mice, not COX-2-deficient mice. PET of rats after intrastriatal injection of lipopolysaccharide showed a significant increase in accumulation of (11)C-ketoprofen methyl ester in the inflamed area. This increase was evident at the early phase of 6 h, peaked at day 1, and then returned to basal levels by day 7. In addition, immunohistochemical analysis revealed that the population of activated microglia and macrophages was elevated at the early phase with COX-1 expression but not COX-2. A significant increase in (11)C-ketoprofen methyl ester accumulation was also observed at day 1 after intrastriatal injection of quinolinic acid, with increased COX-1-expressing activated microglia and macrophages. CONCLUSION: We have identified (11)C-ketoprofen methyl ester as a COX-1-selective PET probe, and using this, we have also demonstrated a time-dependent expression of COX-1 in activated microglia and macrophages during the neuroinflammatory process in the living brain. Thus, COX-1 may play a crucial role in the pathology of neuroinflammation and might be a critical target for the diagnosis and therapy of neurodegenerative disorders.458Soliman, M. L.; Ohm, J. E.; Rosenberger, T. A. Acetate reduces PGE2 release and modulates phospholipase and cyclooxygenase levels in neuroglia stimulated with lipopolysaccharide. Lipids 2013, 48, 651– 662, DOI: 10.1007/s11745-013-3799-x[Crossref], [PubMed], [CAS], Google Scholar458https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXot1Oht7g%253D&md5=e9e4e1dee790b13c2535d3a953e7bbd1Acetate Reduces PGE2 Release and Modulates Phospholipase and Cyclooxygenase Levels in Neuroglia Stimulated with LipopolysaccharideSoliman, Mahmoud L.; Ohm, Joyce E.; Rosenberger, Thad A.Lipids (2013), 48 (7), 651-662CODEN: LPDSAP; ISSN:0024-4201. (Springer)Acetate supplementation attenuates neuroglial activation, increases histone and non-histone protein acetylation, reduces pro-inflammatory cytokine expression, and increases IL-4 transcription in rat models of neuroinflammation and Lyme's neuroborreliosis. Because eicosanoid signaling is involved in neuroinflammation, the authors measured the effect acetate treatment had on phospholipase, cyclooxygenase, and prostaglandin E2 (PGE2) levels in BV-2 microglia and primary astrocytes stimulated with lipopolysaccharide (LPS). In BV-2 microglia, the authors found that LPS increased the phosphorylation-state of cytosolic phospholipase A2 (cPLA2), reduced the levels of phospholipase C (PLC) β1, and increased the levels of cyclooxygenase (Cox)-1 and -2. Acetate treatment returned PLCβ1 and Cox-1 levels to normal, attenuated the increase in Cox-2, but had no effect on cPLA2 phosphorylation. In primary astrocytes, LPS increased the phosphorylation of cPLA2 and increased the levels of Cox-1 and Cox-2. Acetate treatment in these cells reduced secretory PLA2 IIA and PLCβ1 levels as compared to LPS-treatment groups, reversed the increase in cPLA2 phosphorylation, and returned Cox-1 levels to normal. Acetate treatment reduced PGE2 release in astrocytes stimulated with LPS to control levels, but did not alter PGE2 levels in BV-2 microglia. The amt. of acetylated H3K9 bound to the promoter regions of Cox-1, Cox-2, IL-1β and NF-κB p65 genes, but not IL-4 in were increased in BV-2 microglia treated with acetate. These data suggest that acetate treatment can disrupt eicosanoid signaling in neuroglia that may, in part, be the result of altering gene expression due chromatin remodeling as a result of increasing H3K9 acetylation.459Farooqui, A. A.; Horrocks, L. A.; Farooqui, T. Modulation of inflammation in brain: A matter of fat: Neuroinflammation and fatty acids. J. Neurochem. 2007, 101, 577– 599, DOI: 10.1111/j.1471-4159.2006.04371.x[Crossref], [PubMed], [CAS], Google Scholar459https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlsV2ks78%253D&md5=879ddbb62378294c03ec0c3ad7f92b4bModulation of inflammation in brain: a matter of fatFarooqui, Akhlaq A.; Horrocks, Lloyd A.; Farooqui, TahiraJournal of Neurochemistry (2007), 101 (3), 577-599CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)A review. Neuro-inflammation is a host defense mechanism assocd. with neutralization of an insult and restoration of normal structure and function of brain. Neuro-inflammation is a hallmark of all major CNS diseases. The main mediators of neuro-inflammation are microglial cells. These cells are activated during a CNS injury. Microglial cells initiate a rapid response that involves cell migration, proliferation, release of cytokines/chemokines and trophic and/or toxic effects. Cytokines/chemokines stimulate phospholipases A2 and cyclooxygenases. This results in breakdown of membrane glycerophospholipids with the release of arachidonic acid (AA) and docosahexaenoic acid (DHA). Oxidn. of AA produces pro-inflammatory prostaglandins, leukotrienes, and thromboxanes. One of the lyso-glycerophospholipids, the other products of reactions catalyzed by phospholipase A2, is used for the synthesis of pro-inflammatory platelet-activating factor. These pro-inflammatory mediators intensify neuro-inflammation. Lipoxin, an oxidized product of AA through 5-lipoxygenase, is involved in the resoln. of inflammation and is anti-inflammatory. Docosahexaenoic acid is metabolized to resolvins and neuroprotectins. These lipid mediators inhibit the generation of prostaglandins, leukotrienes, and thromboxanes. Levels of prostaglandins, leukotrienes, and thromboxanes are markedly increased in acute neural trauma and neurodegenerative diseases. Docosahexaenoic acid and its lipid mediators prevent neuro-inflammation by inhibiting transcription factor NFκB, preventing cytokine secretion, blocking the synthesis of prostaglandins, leukotrienes, and thromboxanes, and modulating leukocyte trafficking. Depending on its timing and magnitude in brain tissue, inflammation serves multiple purposes. It is involved in the protection of uninjured neurons and removal of degenerating neuronal debris and also in assisting repair and recovery processes. The dietary ratio of AA to DHA may affect neurodegeneration assocd. with acute neural trauma and neurodegenerative diseases. The dietary intake of docosahexaenoic acid offers the possibility of counter-balancing the harmful effects of high levels of AA-derived pro-inflammatory lipid mediators.460Airas, L.; Rissanen, E.; Rinne, J. O. Imaging neuroinflammation in multiple sclerosis using TSPO-PET. Clin Transl Imaging. 2015, 3, 461– 473, DOI: 10.1007/s40336-015-0147-6[Crossref], [PubMed], [CAS], Google Scholar460https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FhtlyrsA%253D%253D&md5=0330c1407a75b8ea6958d28a547c773cImaging neuroinflammation in multiple sclerosis using TSPO-PETAiras Laura; Rissanen Eero; Rinne Juha OClinical and translational imaging (2015), 3 (), 461-473 ISSN:2281-5872.Conventional MR imaging (MRI) techniques form the cornerstone of multiple sclerosis (MS) diagnostics and clinical follow-up today. MRI is sensitive in demonstrating focal inflammatory lesions and diffuse atrophy. However, especially in progressive MS, there is increasingly widespread diffuse pathology also outside the plaques, often related to microglial activation and neurodegeneration. This cannot be detected using conventional MRI. Positron emission tomography (PET) imaging using 18-kDa translocator protein (TSPO) binding radioligands has recently shown promise as a tool to detect this diffuse pathology in vivo, and for the first time allows one to follow its development longitudinally. It is becoming evident that the more advanced the MS disease is, the more pronounced is microglial activation. PET imaging allows the detection of MS-related pathology at molecular level in vivo. It has potential to enable measurement of effects of new disease-modifying drugs aimed at reducing neurodegeneration and neuroinflammation. PET imaging could thus be included in the design of future clinical trials of progressive MS. There are still technical issues related to the quality of TSPO radioligands and post-processing methodology, and comparison of studies from different PET centres is challenging. In this review, we summarise the main evidence supporting the use of TSPO-PET as a tool to explore the diffuse inflammation in MS.461Rissanen, E.; Virta, J. R.; Paavilainen, T.; Tuisku, J.; Helin, S.; Luoto, P.; Parkkola, R.; Rinne, J. O.; Airas, L. Adenosine A2A receptors in secondary progressive multiple sclerosis: A [11C]TMSX brain PET study. J. Cereb. Blood Flow Metab. 2013, 33, 1394– 1401, DOI: 10.1038/jcbfm.2013.85[Crossref], [PubMed], [CAS], Google Scholar461https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWqsbvO&md5=0dbb6f56903273f1ce5a3286e17893ccAdenosine A2A receptors in secondary progressive multiple sclerosis: a [11C]TMSX brain PET studyRissanen, Eero; Virta, Jere R.; Paavilainen, Teemu; Tuisku, Jouni; Helin, Semi; Luoto, Pauliina; Parkkola, Riitta; Rinne, Juha O.; Airas, LauraJournal of Cerebral Blood Flow & Metabolism (2013), 33 (9), 1394-1401CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)In this study, positron emission tomog. (PET) imaging with a radioligand to adenosine A2A receptors (A2AR)-a potent regulator of inflammation-was used to gain insight into the mol. alterations in normal-appearing white matter (NAWM) and gray matter (GM) in secondary progressive multiple sclerosis (SPMS). Normal-appearing white matter and GM, despite seeming normal in conventional magnetic resonance imaging (MRI), are important loci of widespread inflammation, neuronal damage, and source of progressive disability in multiple sclerosis (MS). Dynamic PET imaging using A2AR-specific [11C]TMSX and brain MRI with diffusion tensor imaging were performed to eight SPMS patients and seven healthy controls. Distribution vols. (VT) of [11C]TMSX were analyzed from 13 regions of interest using Logan plot with arterial plasma input. The SPMS patients had significantly increased [11C]TMSX-VT in NAWM compared with controls (mean (s.d.): 0.55 (±0.08) vs. 0.45 (±0.05); P=0.036). Both the increased VT and the decreased fractional anisotropy (FA) in NAWM were assocd. with higher expanded disability status scale (EDSS) scores (P=0.030 and P=0.012, resp.), whereas the T2-lesion load of SPMS patients did not correlate with EDSS. This study shows, that A2ARs are increased in the brain of SPMS patients, and that [11C]TMSX-PET provides a novel approach to learn about central nervous system pathol. in SPMS in vivo.462Stankoff, B.; Freeman, L.; Aigrot, M.-S.; Chardain, A.; Dollé, F.; Williams, A.; Galanaud, D.; Armand, L.; Lehericy, S.; Lubetzki, C.; Zalc, B.; Bottlaender, M. Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-11C]-2-(4′-methylaminophenyl)- 6-hydroxybenzothiazole. Ann. Neurol. 2011, 69, 673– 680, DOI: 10.1002/ana.22320[Crossref], [PubMed], [CAS], Google Scholar462https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltVygtLs%253D&md5=adaa87c73a372d900c81c2f7082f1a73Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-11C]-2-(4'-methylaminophenyl)- 6-hydroxybenzothiazoleStankoff, Bruno; Freeman, Leorah; Aigrot, Marie-Stephane; Chardain, Audrey; Dolle, Frederic; Williams, Anna; Galanaud, Damien; Armand, Lucie; Lehericy, Stephane; Lubetzki, Catherine; Zalc, Bernard; Bottlaender, MichelAnnals of Neurology (2011), 69 (4), 673-680CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)Objective: Imaging of myelin tracts in vivo would greatly improve the monitoring of demyelinating diseases such as multiple sclerosis (MS). To date, no imaging technique specifically targets demyelination and remyelination. Recently, amyloid markers related to Congo red have been shown to bind to central nervous system (CNS) myelin. Here we questioned whether the thioflavine-T deriv. 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), which also binds to amyloid plaques, could serve as a myelin marker. Methods: PIB fixation to myelin was studied by fluorescence in the normal and dysmyelinating mouse brain, as well as in the postmortem brain of MS patients. Positron emission tomog. (PET) expts. were conducted using [11C]PIB in baboons and in a proof of concept clin. study in 2 MS patients. Results: Applied directly on tissue sections or after i.p. injection, PIB stained CNS myelin, and the decrease in the level of fixation paralleled the amt. of myelin loss in a dysmyelinating mutant. In normally myelinated areas of postmortem MS brain, demyelinated and remyelinated lesions were clearly distinguishable by the differential intensity of labeling obsd. with PIB. PET using i.v. injected radiolabeled [11C]PIB imaged CNS myelin in baboons and humans. In MS patients, the dynamic anal. of PET acquisitions allowed quant. assessment of demyelination. Interpretation: PIB could be used as an imaging marker to quantify myelin loss and repair in demyelinating diseases.463Baron, J.-C.; Yamauchi, H.; Fujioka, M.; Endres, M. Selective neuronal loss in ischemic stroke and cerebrovascular disease. J. Cereb. Blood Flow Metab. 2014, 34, 2– 18, DOI: 10.1038/jcbfm.2013.188[Crossref], [PubMed], [CAS], Google Scholar463https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7jtFCqsw%253D%253D&md5=685ccc761936b5b0cb4ceaeede503528Selective neuronal loss in ischemic stroke and cerebrovascular diseaseBaron Jean-Claude; Yamauchi Hiroshi; Fujioka Masayuki; Endres MatthiasJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (2014), 34 (1), 2-18 ISSN:.As a sequel of brain ischemia, selective neuronal loss (SNL)-as opposed to pannecrosis (i.e. infarction)-is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and (11)C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary 'exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences-including the impact on neurological recovery and contribution to vascular cognitive impairment-association with possible causal processes such as microglial activation, and preventability of SNL.464Pascual, B.; Prieto, E.; Arbizu, J.; Marti-Climent, J. M.; Peñuelas, I.; Quincoces, G.; Zarauza, R.; Pappatà, S.; Masdeu, J. C. Decreased carbon-11-flumazenil binding in early Alzheimer’s disease. Brain 2012, 135, 2817– 2825, DOI: 10.1093/brain/aws210[Crossref], [PubMed], [CAS], Google Scholar464https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bltlyltQ%253D%253D&md5=b8fb6d1925ce2871268f67840bb9f6feDecreased carbon-11-flumazenil binding in early Alzheimer's diseasePascual Belen; Prieto Elena; Arbizu Javier; Marti-Climent Josep M; Penuelas Ivan; Quincoces Gemma; Zarauza Rosina; Pappata Sabina; Masdeu Joseph CBrain : a journal of neurology (2012), 135 (Pt 9), 2817-25 ISSN:.Neuronal loss in Alzheimer's disease, a better correlate of cognitive impairment than amyloid deposition, is currently gauged by the degree of regional atrophy. However, functional markers, such as GABA(A) receptor density, a marker of neuronal integrity, could be more sensitive. In post-mortem hippocampus, GABA(A) messenger RNA expression is reduced even in mild cognitive impairment. We measured whole-brain GABA(A) binding potential in vivo using [(11)C]-flumazenil positron emission tomography and compared GABA(A) binding with metabolic and volumetric measurements. For this purpose, we studied 12 subjects, six patients with early Alzheimer's disease and six healthy controls, with [(11)C]-flumazenil and [(18)F]-fluorodeoxyglucose positron emission tomography, as well as with high-resolution magnetic resonance imaging. Data were evaluated with both voxel-based parametric methods and volume of interest methods. We found that in early Alzheimer's disease, with voxel-based analysis, [(11)C]-flumazenil binding was decreased in infero-medial temporal cortex, retrosplenial cortex and posterior perisylvian regions. Inter-group differences reached corrected significance when using an arterial input function. Metabolism measured with positron emission tomography and volumetric measurements obtained with magnetic resonance imaging showed changes in regions affected in early Alzheimer's disease, but, unlike with [(11)C]-flumazenil binding and probably due to sample size, the voxel-based findings failed to reach corrected significance in any region of the brain. With volume of interest analysis, hippocampi and posterior cingulate gyrus showed decreased [(11)C]-flumazenil binding. In addition, [(11)C]-flumazenil hippocampal binding correlated with memory performance. Remarkably, [(11)C]-flumazenil binding was decreased precisely in the regions showing the greatest degree of neuronal loss in post-mortem studies of early Alzheimer's disease. From these data, we conclude that [(11)C]-flumazenil binding could be a useful marker of neuronal loss in early Alzheimer's disease.
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- Rubel Chakravarty, Sudipta Chakraborty. Production of a broad palette of positron emitting radioisotopes using a low-energy cyclotron: Towards a new success story in cancer imaging?. Applied Radiation and Isotopes 2021, 176 , 109860. https://doi.org/10.1016/j.apradiso.2021.109860
Abstract
Figure 1
Figure 1. Commonly used PET radiotracers for diagnosis under various clinical conditions.
Figure 2
Figure 2. Cyclotron production and β+-decay process of carbon-11 radionuclide.
Figure 3
Figure 3. Transformation of different precursors from carbon-11 radionuclide.
Figure 4
Figure 4. Reaction pathways for [11C]CO2 fixation into urea, carbamates, oxazolidinones, carboxylic acids, amides, and their carbon-11 radiotracer derivatives.
Figure 5
Figure 5. Reaction pathways for generation of secondary precursors and their carbon-11 radiotracer derivatives.
Figure 6
Figure 6. Carbon-11 radiotracers through C–C bond formation from various well-known reaction mechanisms.
Figure 7
Figure 7. List of various target-specific carbon-11 radiotracers in oncology.
Figure 8
Figure 8. List of various target-specific carbon-11 radiotracers in cardiology.
Figure 9
Figure 9. List of various target-specific carbon-11 radiotracers for brain imaging.
Figure 10
Figure 10. List of various target-specific carbon-11 radiotracers for neuroinflammation.
References
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- 2Matthews, P. M.; Rabiner, E. A.; Passchier, J.; Gunn, R. N. Positron emission tomography molecular imaging for drug development: PET for drug development. Br. J. Clin. Pharmacol. 2012, 73, 175– 186, DOI: 10.1111/j.1365-2125.2011.04085.x[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtlSqtbo%253D&md5=aa03299a6a0345a9435a3980acc4af77Positron emission tomography molecular imaging for drug developmentMatthews, Paul M.; Rabiner, Eugenii A.; Passchier, Jan; Gunn, Roger N.British Journal of Clinical Pharmacology (2012), 73 (2), 175-186CODEN: BCPHBM; ISSN:0306-5251. (Wiley-Blackwell)A review. Human in vivo mol. imaging with positron emission tomog. (PET) enables a new kind of precision pharmacol., able to address questions central to drug development. Biodistribution studies with drug mols. carrying positron-emitting radioisotopes can test whether a new chem. entity reaches a target tissue compartment (such as the brain) in sufficient amts. to be pharmacol. active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concn. and target occupancy. Tailored radiotracers can be used to measure relative rates of biol. processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows mol. interactions to be related directly to anatomical or physiol. changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging exptl. medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational mol. imaging strategy be considered routinely and at the earliest stages of new drug development.
- 3Goud, N. S.; Kanth Makani, V. K.; Pranay, J.; Alvala, R.; Qureshi, I. A.; Kumar, P.; Bharath, R. D.; Nagaraj, C.; Yerramsetty, S.; Pal-Bhadra, M.; Alvala, M. Synthesis, 18F- radiolabeling and apoptosis inducing studies of novel 4, 7-disubstituted coumarins. Bioorg. Chem. 2020, 97, 103663, DOI: 10.1016/j.bioorg.2020.103663[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjvVKgsr4%253D&md5=eb06c1662428a62783e8607c22290695Synthesis, 18F-radiolabeling and apoptosis inducing studies of novel 4,7-disubstituted coumarinsGoud, Nerella Sridhar; Kanth Makani, Venkata Krishna; Pranay, Jakkula; Alvala, Ravi; Qureshi, Insaf A.; Kumar, Pardeep; Bharath, Rose Dawn; Nagaraj, Chandana; Yerramsetty, Suresh; Pal-Bhadra, Manika; Alvala, MallikaBioorganic Chemistry (2020), 97 (), 103663CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)A new series of 4,7-disubstituted coumarin derivs. I [R1 = morpholin-4-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 4-methylpiperidin-1-yl, etc.; R2 = cyanomethyl, (4-methoxyphenyl)methyl, (4-bromophenyl)methyl, etc.] have been synthesized as galectin-1 targeting apoptosis inducing agents and evaluated for their in vitro cytotoxic potentials against a panel of selected human cancer cell lines namely, Brest (MCF7), Ovarian (SKOV3), Prostate (PC-3 & DU145) and normal embryonic kidney (HEK293T) cells, using MTT assay. Most of the compds. I exhibited potent growth inhibitory action against the treated cancer cell lines with an IC50 range of 10-30μM. Compd. I [R1 = 4-ethoxycarbonyl-piperidin-1-yl; R2 = (4-nitrophenyl)methyl (A)] exhibited a significant growth inhibition against prostate cancer (PC-3 & DU145) cell lines with an IC50 value of 7.45 ± 0.03μM, 8.95 ± 0.17μM resp. Further, the target compd. A was radiolabeled with fluorine-18 [18F] to be used as a novel PET radiotracer for imaging of tumors via targeting galectin-1, using appropriate reaction conditions in the GE Tracer-lab FX2N synthesis module. The purifn. of the [18F] radiolabeled compd. II was successfully achieved with 60% ethanol. The radiochem. purity was >85% and residual solvent limit of DMF was 65 ± 3 ppm as analyzed by HPLC, TLC & GC anal. methods. The apoptosis studies confirm the inhibition of cell proliferation with morphol. changes like cell shrinkage, blebbing and cell wall deformation, increasing the ROS levels, and loss of mitochondrial membrane potential by Acridine orange/Ethidium bromide staining, Hoechst-33342 staining, H2DCFDA staining, annexin V-FITC/PI, and JC-1 staining methods. In flow cytometric anal., the sub-G1 phase of the cell cycle is selectively arrested in a dose-dependent manner. In Gal-1 ELISA studies, compd. A efficiently reduced the levels of Gal-1 protein in dose-dependent manner with an IC50 value of 100μM. The binding const. (Ka) of A with Gal-1 was obsd. as 1.3 × 104 M-1 by fluorescence spectroscopy. The mol. docking studies clearly showed possible interactions and the pharmacokinetic (ADMET) properties of compd. A with Gal-1. The novel 4,7-disubstituted coumarins I could be a potential cytotoxic and PET imaging agents via Gal-1.
- 4Deng, X.; Rong, J.; Wang, L.; Vasdev, N.; Zhang, L.; Josephson, L.; Liang, S. H. Chemie Der Positronenemissionstomographie: Aktuelle Fortschritte Bei 11 C-, 18 F-, 13 N- Und 15O-Markierungsreaktionen. Angew. Chem. 2019, 131, 2604– 2631, DOI: 10.1002/ange.201805501
- 5Goud, N. S.; Joshi, R. K.; Bharath, R. D.; Kumar, P. Fluorine-18: a radionuclide with diverse range of radiochemistry and synthesis strategies for target based PET diagnosis. Eur. J. Med. Chem. 2020, 187, 111979, DOI: 10.1016/j.ejmech.2019.111979[Crossref], [PubMed], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVKnsLrM&md5=baea587e0b3b5cd17e7a42e9ce9147afFluorine-18: A radionuclide with diverse range of radiochemistry and synthesis strategies for target based PET diagnosisGoud, Nerella Sridhar; Joshi, Raman Kumar; Bharath, Rose Dawn; Kumar, PardeepEuropean Journal of Medicinal Chemistry (2020), 187 (), 111979CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Fluorine-18 is one of the most widely used radionuclides for the prodn. of radiopharmaceuticals for positron emission tomog. (PET). The radiolabeling methods like nucleophilic, electrophilic, Cu mediated mechanisms or prosthetic groups are widely using to achieve high regioselective radiochem. yields. It acts as a powerful tool to identify new drug targets through cellular uptake, pharmacokinetic (ADME) and pharmacodynamic parameters of the 18F labeled tracer or drug. These PET tracers have been developed based on the receptors expressed in a disease condition. A no. of 18F radiotracers have been developed against the Tropomyosin Receptor Kinases (Trks), Carbonic anhydrases (CAs), Epidermal Growth Factor Receptors (EGFR), Poly ADP ribose polymerase (PARP) etc. for the diagnosis in cancer therapy. The current research also focused on the development of novel 18F radiotracers for neurol. conditions for deciphering underlying physiol. in diseases like Alzheimer, and Parkinson. Therefore, in this review we have focused on 18F labeling methods, and radiotracers developed against common cancers and neurol. conditions.
- 6Musafargani, S.; Ghosh, K. K.; Mishra, S.; Mahalakshmi, P.; Padmanabhan, P.; Gulyás, B. PET/MRI: A frontier in era of complementary hybrid imaging. European Journal of Hybrid Imaging. 2018, 2, 12, DOI: 10.1186/s41824-018-0030-6[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FntlCltw%253D%253D&md5=5b996e5ecfcb80ff2ff0043aacda8c06PET/MRI: a frontier in era of complementary hybrid imagingMusafargani Sikkandhar; Ghosh Krishna Kanta; Mishra Sachin; Padmanabhan Parasuraman; Gulyas Balazs; Mahalakshmi PachaiyappanEuropean journal of hybrid imaging (2018), 2 (1), 12 ISSN:.With primitive approaches, the diagnosis and therapy were operated at the cellular, molecular, or even at the genetic level. As the diagnostic techniques are more concentrated towards molecular level, multi modal imaging becomes specifically essential. Multi-modal imaging has extensive applications in clinical as well as in pre-clinical studies. Positron Emission Tomography (PET) has flourished in the field of nuclear medicine, which has motivated it to fuse with Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) for PET/CT and PET/MRI respectively. However, the challenges in PET/CT are due to the inability of simultaneous acquisition and reduced soft tissue contrast, which has led to the development of PET/MRI. Also, MRI offers the better soft tissue contrast over CT. Hence, fusion of PET and MRI results in combining structural information with functional image from PET. Yet, it has many technical challenges due to the interference between the modalities. Also, it must be resolved with various approaches for addressing the shortcomings of each system and improvise on the image quantification system. This review elaborates on the various challenges in the present PET/MRI system and the future directions of the hybrid modality. Also, the different data acquisition and analysis techniques of PET/MRI system are discussed with enhanced details on the software tools.
- 7Vaquero, J. J.; Kinahan, P. Positron emission tomography: Current challenges and opportunities for technological advances in clinical and preclinical imaging systems. Annu. Rev. Biomed. Eng. 2015, 17, 385– 414, DOI: 10.1146/annurev-bioeng-071114-040723[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFOqsLzP&md5=f5f8d8b4839e0ad12663b9245f3702c1Positron Emission Tomography: Current Challenges and Opportunities for Technological Advances in Clinical and Preclinical Imaging SystemsVaquero, Juan Jose; Kinahan, PaulAnnual Review of Biomedical Engineering (2015), 17 (), 385-414CODEN: ARBEF7; ISSN:1523-9829. (Annual Reviews)A review. Positron emission tomog. (PET) imaging is based on detecting two time-coincident high-energy photons from the emission of a positron-emitting radioisotope. The physics of the emission, and the detection of the coincident photons, give PET imaging unique capabilities for both very high sensitivity and accurate estn. of the in vivo concn. of the radiotracer. PET imaging has been widely adopted as an important clin. modality for oncol., cardiovascular, and neurol. applications. PET imaging has also become an important tool in preclin. studies, particularly for investigating murine models of disease and other small-animal models. However, there are several challenges to using PET imaging systems. These include the fundamental trade-offs between resoln. and noise, the quant. accuracy of the measurements, and integration with X-ray computed tomog. and magnetic resonance imaging. In this article, we review how researchers and industry are addressing these challenges.
- 8Lecchi, M.; Fossati, P.; Elisei, F.; Orecchia, R.; Lucignani, G. Current concepts on imaging in radiotherapy. Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 821– 837, DOI: 10.1007/s00259-007-0631-y[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c7ovVyltg%253D%253D&md5=c3d508c7acd06bb644c32e382e8c8ae1Current concepts on imaging in radiotherapyLecchi Michela; Fossati Piero; Elisei Federica; Orecchia Roberto; Lucignani GiovanniEuropean journal of nuclear medicine and molecular imaging (2008), 35 (4), 821-37 ISSN:1619-7070.New high-precision radiotherapy (RT) techniques, such as intensity-modulated radiation therapy (IMRT) or hadrontherapy, allow better dose distribution within the target and spare a larger portion of normal tissue than conventional RT. These techniques require accurate tumour volume delineation and intrinsic characterization, as well as verification of target localisation and monitoring of organ motion and response assessment during treatment. These tasks are strongly dependent on imaging technologies. Among these, computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography (US) and positron emission tomography (PET) have been applied in high-precision RT. For tumour volume delineation and characterization, PET has brought an additional dimension to the management of cancer patients by allowing the incorporation of crucial functional and molecular images in RT treatment planning, i.e. direct evaluation of tumour metabolism, cell proliferation, apoptosis, hypoxia and angiogenesis. The combination of PET and CT in a single imaging system (PET/CT) to obtain a fused anatomical and functional dataset is now emerging as a promising tool in radiotherapy departments for delineation of tumour volumes and optimization of treatment plans. Another exciting new area is image-guided radiotherapy (IGRT), which focuses on the potential benefit of advanced imaging and image registration to improve precision, daily target localization and monitoring during treatment, thus reducing morbidity and potentially allowing the safe delivery of higher doses. The variety of IGRT systems is rapidly expanding, including cone beam CT and US. This article examines the increasing role of imaging techniques in the entire process of high-precision radiotherapy.
- 9Kostakoglu, L.; Agress, H.; Goldsmith, S. J. Clinical role of FDG PET in evaluation of cancer patients. Radio Graphics. 2003, 23, 315– 340, DOI: 10.1148/rg.232025705
- 10Been, L. B.; Suurmeijer, A. J. H.; Cobben, D. C. P.; Jager, P. L.; Hoekstra, H. J.; Elsinga, P. H. [18F]FLT-PET in oncology: Current status and opportunities. Eur. J. Nucl. Med. Mol. Imaging 2004, 31, 1659– 1672, DOI: 10.1007/s00259-004-1687-6[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cngvVKrug%253D%253D&md5=749bd7572d93eed431023cd1041973bd18F]FLT-PET in oncology: current status and opportunitiesBeen Lukas B; Suurmeijer Albert J H; Cobben David C P; Jager Pieter L; Hoekstra Harald J; Elsinga Philip HEuropean journal of nuclear medicine and molecular imaging (2004), 31 (12), 1659-72 ISSN:1619-7070.In recent years, [18F]-fluoro-3'-deoxy-3'-L: -fluorothymidine ([18F]FLT) has been developed as a proliferation tracer. Imaging and measurement of proliferation with PET could provide us with a non-invasive staging tool and a tool to monitor the response to anticancer treatment. In this review, the basis of [18F]FLT as a proliferation tracer is discussed. Furthermore, an overview of the current status of [18F]FLT-PET research is given. The results of this research show that although [18F]FLT is a tracer that visualises cellular proliferation, it also has certain limitations. In comparison with the most widely used PET tracer, [18F]FDG, [18F]FLT uptake is lower in most cases. Furthermore, [18F]FLT uptake does not always reflect the tumour cell proliferation rate, for example during or shortly after certain chemotherapy regimens. The opportunities provided by, and the limitations of, [18F]FLT as a proliferation tracer are addressed in this review, and directions are given for further research, taking into account the strong and weak points of the new tracer.
- 11Richardson, M. P.; Koepp, M. J.; Brooks, D. J.; Duncan, J. S. 11C-flumazenil PET in neocortical epilepsy. Neurology 1998, 51, 485– 492, DOI: 10.1212/WNL.51.2.485[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXls1Wqtr0%253D&md5=76224abba31a5d69bbb6e8be42aedd4111C-flumazenil PET in neocortical epilepsyRichardson, M. P.; Koepp, M. J.; Brooks, D. J.; Duncan, J. S.Neurology (1998), 51 (2), 485-492CODEN: NEURAI; ISSN:0028-3878. (Lippincott-Raven Publishers)Objective: To investigate focal cortical abnormalities of γ-aminobutyric acid type A-central benzodiazepine receptors (GABAA-cBZRs) in patients with extratemporal partial seizures with acquired lesions and in patients with normal high-resoln. MRI. Methods: Six patients with acquired lesions and 18 patients with normal high-resoln. MRI and extratemporal partial seizures, as well as 24 normal controls, were studied with 11C-flumazenil (FMZ) PET to produce voxel-by-voxel images of FMZ vol. of distribution (FMZVD), which reflects d. of GABAA-cBZRs. These images were analyzed using Statistical Parametric Mapping (SPM). Each patient was compared with the control group to reveal regions with abnormal FMZVD at p < 0.001 uncorrected, cor. to p < 0.05 for the whole brain vol. Each normal control was compared with the remaining controls in the same manner. Results: All six patients with acquired lesions had a single region of reduced FMZVD. Thirteen of 18 patients with normal MRI had regions of abnormal cortical FMZVD: 10 had regions of increased FMZVD, 6 had regions of decreased FMZVD, and 3 had both regions of increased and decreased FMZVD. Seven patients had an abnormality in the lobe and 12 in the hemisphere of presumed seizure origin. Conclusions: FMZ PET analyzed with SPM is an automated, objective, sensitive, and specific means for detecting regional cortical abnormalities of GABAA-cBZRs in patients with partial seizures. This technique may be useful in the evaluation of patients with refractory partial seizures for surgical treatment, particularly in those patients with normal MRI.
- 12Hirvonen, J.; Aalto, S.; Lumme, V.; Någren, K.; Kajander, J.; Vilkman, H.; Hagelberg, N.; Oikonen, V.; Hietala, J. Measurement of striatal and thalamic dopamine D2 receptor binding with 11C-raclopride. Nucl. Med. Commun. 2003, 24, 1207– 1214, DOI: 10.1097/00006231-200312000-00002[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXptV2jt7c%253D&md5=2e36c9233157203fb37378d6a2efd8ecMeasurement of striatal and thalamic dopamine D2 receptor binding with 11C-racloprideHirvonen, J.; Aalto, S.; Lumme, V.; Nagren, K.; Kajander, J.; Vilkman, H.; Hagelberg, N.; Oikonen, V.; Hietala, J.Nuclear Medicine Communications (2003), 24 (12), 1207-1214CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)11C-Raclopride is a widely used positron emission tomog. (PET) tracer for measurement of striatal D2 dopamine receptor binding characteristics. Recently, 11C-raclopride has also been used for quantification of thalamic D2 receptor binding. We studied reproducibility and validity issues on the thalamic D2 binding measurements using healthy volunteer test-retest data and simulated data. Eight healthy male volunteers received 11C-raclopride as a bolus injection in a std. test-retest design using 3-dimensional PET. The displacement of thalamic 11C-raclopride binding by the D2 receptor antagonist haloperidol was studied in two female schizophrenic patients. With regards to reproducibility and reliability, thalamic 11C-raclopride binding could be described with a simplified ref. tissue model resulting in binding potentials (BPs) between 0.38 and 0.66. In comparison, the model failed to describe 11C-raclopride binding consistently in temporal cortex due to low specific signal. Measurement of thalamic 11C-raclopride BP was reproducible with a test-retest variability of 7.6±6.2% and reliable with an intraclass correlation coeff. (ICC) of 0.87. Comparable ICCs were obsd. in caudate and putamen (0.84-0.96). With regard to validity, subchronic low dose haloperidol treatment reduced specific 11C-raclopride binding equally in putamen and thalamus but a higher dose induced clearly higher D2 receptor occupancy in putamen than in thalamus. Noise simulations indicated that this can partly be explained by an over-estn. of thalamic D2 receptor BP in noisy conditions (low signal, high occupancy). The D2 receptor BP in putamen was clearly more resistant to noise. We conclude that the reproducibility and reliability of thalamic 11C-raclopride BP is good and equal to, or only slightly less than, those obsd. in caudate or putamen. However, the signal-to-noise ratio for quantification may become too low esp. in receptor occupancy-type studies, leading to an artifactual underestimation of measured D2 receptor occupancy.
- 13Glaudemans, A. W. J. M.; Enting, R. H.; Heesters, M. A. A. M.; Dierckx, R. A. J. O.; van Rheenen, R. W. J.; Walenkamp, A. M. E.; Slart, R. H. J. A. Value of 11C-methionine PET in imaging brain tumours and metastases. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 615– 635, DOI: 10.1007/s00259-012-2295-5[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjslOgsbs%253D&md5=2167374e019d48fc0b10ac25625074d3Value of 11C-methionine PET in imaging brain tumours and metastasesGlaudemans, Andor W. J. M.; Enting, Roelien H.; Heesters, Mart A. A. M.; Dierckx, Rudi A. J. O.; Rheenen, Ronald W. J.; Walenkamp, Annemiek M. E.; Slart, Riemer H. J. A.European Journal of Nuclear Medicine and Molecular Imaging (2013), 40 (4), 615-635CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. 11C-methionine (MET) is the most popular amino acid tracer used in PET imaging of brain tumors. Because of its characteristics, MET PET provides a high detection rate of brain tumors and good lesion delineation. This review focuses on the role of MET PET in imaging cerebral gliomas. The Introduction provides a clin. overview of what is important in primary brain tumors, recurrent brain tumors and brain metastases. The indications for radiotherapy and the results and problems arising after chemoradiotherapy in relation to imaging (pseudoprogression or radionecrosis) are discussed. The working mechanism, scan interpretation and quantification possibilities of MET PET are then explained. A literature overview is given of the role of MET PET in primary gliomas (diagnostic accuracy, grading, prognosis, assessment of tumor extent, biopsy and radiotherapy planning), in brain metastases, and in the differentiation between tumor recurrence and radiation necrosis. Finally, MET PET is compared to other nuclear imaging possibilities in brain tumor imaging.
- 14Welle, C. L.; Cullen, E. L.; Peller, P. J.; Lowe, V. J.; Murphy, R. C.; Johnson, G. B.; Binkovitz, L. A. 11 C-Choline PET/CT in recurrent prostate cancer and nonprostatic neoplastic processes. Radio Graphics. 2016, 36, 279– 292, DOI: 10.1148/rg.2016150135
- 15Sridhar Goud, N.; Pooladanda, V.; Muni Chandra, K.; Lakshmi Soukya, P. S.; Alvala, R.; Kumar, P.; Nagaraj, C.; Dawn Bharath, R.; Qureshi, I. A.; Godugu, C.; Alvala, M. Novel benzimidazole-triazole hybrids as apoptosis inducing agents in lung cancer: Design, synthesis, 18F-radiolabeling & galectin-1 inhibition studies. Bioorg. Chem. 2020, 102, 104125, DOI: 10.1016/j.bioorg.2020.104125[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFWju7nE&md5=ab2951bd894bb4089cac3982d7980c87Novel benzimidazole-triazole hybrids as apoptosis inducing agents in lung cancer: Design, synthesis, 18F-radiolabeling & galectin-1 inhibition studiesSridhar Goud, Nerella; Pooladanda, Venkatesh; Muni Chandra, K.; Lakshmi Soukya, P. S.; Alvala, Ravi; Kumar, Pardeep; Nagaraj, Chandana; Dawn Bharath, Rose; Qureshi, Insaf A.; Godugu, Chandraiah; Alvala, MallikaBioorganic Chemistry (2020), 102 (), 104125CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)A new series of benzimidazole-triazole hybrids I [R = Ph, benzyl, 1-naphthyl, etc.] as galectin-1 (gal-1) mediated apoptosis-inducing agents were synthesized and evaluated for their potential anticancer activity against a panel of human cancer cell lines viz. breast cancer (MCF-7 and MDA-MB-231), lung cancer (A-549 and NCI-H460), and human keratinocyte cancer (HaCaT) using MTT assay. The target compd. I [R = 3-hydroxyphenyl] exhibited an excellent growth inhibition against lung cancer (A-549 and NCI-H460) cells with an IC50 value of 0.63 ± 0.21μM, and 0.99 ± 0.01μM resp. The target compd. I [R = 3-hydroxyphenyl] also showed a significant growth inhibition against breast cancer (MCF-7 and MDA-MB-23) with an IC50 value of 1.3 ± 0.18μM, and 0.94 ± 0.02μM resp. In addn., the radiochem. synthesis was performed using fluorine-18 radionuclide in the GE Tracer-lab FX2N module to prove the target compd. I [R = 3-hydroxyphenyl] as a PET imaging agent. In the final stage, the 18F-I [R = 3-hydroxyphenyl] target compd. was successfully purified with 60% ethanol in water. The radiochem. purity was achieved >95% using HPLC and the residual solvent DMF limit was around 78 ± 3 ppm confirmed by GC anal. Further, the apoptosis induction by I [R = 3-hydroxyphenyl] in lung cancer (A-549) cells was confirmed as a result of the decrease in MMP levels, increased percentage of apoptotic cells and sub G1 phase arrest by JC-1 staining, DAPI staining, annexin V-FITC/PI and flow cytometric anal. In addn., the target compd. I [R = 3-hydroxyphenyl] significantly reduced the gal-1 protein levels in a dose-dependent manner as confirmed by ELISA studies. The protein binding studies like Surface Plasmon Resonance (SPR) and Fluorescence Spectroscopy (FS) studies indicated that the target compd. I [R = 3-hydroxyphenyl] is capable of binding to gal-1 with an equil. const. (KD) value of 1.19E-06 M and binding const. (Ka) of 9.5 x 103 M-1 resp. The in-silico computational studies also revealed possible interactions and pharmacokinetic properties (ADMET) of compd. I [R = 3-hydroxyphenyl] with the binding domain of gal-1. Therefore, the novel benzimidazole-triazole hybrids I as apoptosis-inducing agents in lung cancer would be potential cytotoxic and PET imaging agents via gal-1.
- 16Tu, Z.; Mach, R. H. C-11 radiochemistry in cancer imaging applications. Curr. Top. Med. Chem. 2010, 10, 1060– 1095, DOI: 10.2174/156802610791384261[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovFaqs7o%253D&md5=75c9b8aedd01b1f8b7917c30c77f6e63C-11 radiochemistry in cancer imaging applicationsTu, Z.; Mach, R. H.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (11), 1060-1095CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. Carbon-11 (C-11) radiotracers are widely used for the early diagnosis of cancer, monitoring therapeutic response to cancer treatment, and pharmacokinetic investigations of anticancer drugs. PET imaging permits non-invasive monitoring of metabolic processes and mol. targets, while carbon-11 radiotracers allow a "hot for cold" substitution of biol. active mols. Advances in org. synthetic chem. and radiochem. as well as improved automated techniques for radiosynthesis have encouraged investigators in developing carbon-11 tracers for use in oncol. imaging studies. The short half-life of carbon-11 (20.38 min) creates special challenges for the synthesis of C-11 labeled tracers; these include the challenges of synthesizing C-11 target compds. with high radiochem. yield, high radiochem. purity and high specific activity in a short time and on a very small scale. The optimization of conditions for making a carbon-11 tracer include the late introduction of the C-11 isotope, the rapid formation and purifn. of the target compd., and the use of automated systems to afford a high yield of the target compd. in a short time. In this review paper, we first briefly introduce some basic principles of PET imaging of cancer; we then discuss principles of carbon-11 radiochem., focus on specific advances in radiochem., and describe the synthesis of C-11 radiopharmaceuticals developed for cancer imaging. The carbon-11 radiochem. approaches described include the N,O, and S-alkylations of [11C]methyl iodide/[11C]methyl triflate and analogs of [11C]methyl iodide and their applications for making carbon-11 tracers; we then address recent advances in exploring a transmetallic complex mediated [11C]carbonyl reaction for oncol. targets.
- 17Andersson, J.; Truong, P.; Halldin, C. In-target produced [11C]methane: Increased specific radioactivity. Appl. Radiat. Isot. 2009, 67, 106– 110, DOI: 10.1016/j.apradiso.2008.09.010[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjmsVWqtw%253D%253D&md5=33616267a39cd427186f4e2995fa723eIn-target produced [11C]methane: Increased specific radioactivityAndersson Jan; Truong Phong; Halldin ChristerApplied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine (2009), 67 (1), 106-10 ISSN:.The (14)N(rho, alpha)(11)C reaction on N(2)-O(2) or N(2)-H(2) gaseous systems as targets in proton bombardment allows for the production of [(11)C]CO(2) and [(11)C]CH(4.) We report the target production of [(11)C]CH(4) and the gas phase iodination to produce [(11)C]CH(3)I with high specific radioactivity (SA). SA was calculated for four different radiopharmaceuticals produced in-house from both target produced [(11)C]CO(2) and [(11)C]CH(4.) For [(11)C]raclopride we obtained an average SA of 3908 GBq/mumol (106000 Ci/mmol) at the end of bombardment for the last 52 productions, which is a 32-fold increase compared to when using the in-house [(11)C]CO(2) target.
- 18Hara, T.; Iio, M. On-line synthesis of [11C]cyanide from cyclotron-produced [11C]carbon dioxide. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1987, 38, 1092– 1093, DOI: 10.1016/0883-2889(87)90077-3
- 19Coenen, H. H.; Gee, A. D.; Adam, M.; Antoni, G.; Cutler, C. S.; Fujibayashi, Y.; Jeong, J. M.; Mach, R. H.; Mindt, T. L.; Pike, V. W.; Windhorst, A. D. Consensus nomenclature rules for radiopharmaceutical chemistry — Setting the record straight. Nucl. Med. Biol. 2017, 55, v– xi, DOI: 10.1016/j.nucmedbio.2017.09.004
- 20Pike, V. W. PET Radiotracers: Crossing the blood–brain barrier and surviving metabolism. Trends Pharmacol. Sci. 2009, 30, 431– 440, DOI: 10.1016/j.tips.2009.05.005[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpt1KgsLg%253D&md5=97704995fecd968baf1e0892bf70324ePET radiotracers: crossing the blood-brain barrier and surviving metabolismPike, Victor W.Trends in Pharmacological Sciences (2009), 30 (8), 431-440CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)A review. Radiotracers for imaging protein targets in the living human brain with positron emission tomog. (PET) are increasingly useful in clin. research and in drug development. Such radiotracers must fulfill many criteria, among which an ability to enter brain adequately and reversibly without contamination by troublesome radiometabolites is desirable for accurate measurement of the d. of a target protein (e.g. neuroreceptor, transporter, enzyme or plaque). Candidate radiotracers can fail as a result of poor passive brain entry, rejection from brain by efflux transporters or undesirable metab. These issues are reviewed. Emerging PET radiotracers for measuring efflux transporter function and new strategies for ameliorating radiotracer metab. are discussed. A growing understanding of the mol. features affecting the brain penetration, metab. and efflux transporter sensitivity of prospective radiotracers should ultimately lead to their more rational and efficient design, and also to their greater efficacy.
- 21Synowiecki, M. A.; Perk, L. R.; Nijsen, J. F. W. Production of novel diagnostic radionuclides in small medical cyclotrons. EJNMMI Radiopharmacy and Chemistry. 2018, 3, 3, DOI: 10.1186/s41181-018-0038-z[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mrns1Wjtg%253D%253D&md5=44e838388dca94875af39bd0ce3679e7Production of novel diagnostic radionuclides in small medical cyclotronsSynowiecki Mateusz Adam; Perk Lars Rutger; Nijsen J Frank WEJNMMI radiopharmacy and chemistry (2018), 3 (1), 3 ISSN:.The global network of cyclotrons has expanded rapidly over the last decade. The bulk of its industrial potential is composed of small medical cyclotrons with a proton energy below 20 MeV for radionuclides production. This review focuses on the recent developments of novel medical radionuclides produced by cyclotrons in the energy range of 3 MeV to 20 MeV. The production of the following medical radionuclides will be described based on available literature sources: Tc-99 m, I-123, I-124, Zr-89, Cu-64, Ga-67, Ga-68, In-111, Y-86 and Sc-44. Remarkable developments in the production process have been observed in only some cases. More research is needed to make novel radionuclide cyclotron production available for the medical industry.
- 22Funk, T.; Sun, M.; Hasegawa, B. H. Radiation dose estimate in small animal SPECT and PET. Med. Phys. 2004, 31, 2680– 2686, DOI: 10.1118/1.1781553[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnsVChsrw%253D&md5=eb10ef8e6140565e4b85e5324e39823cRadiation dose estimate in small animal SPECT and PETFunk, Tobias; Sun, Mingshan; Hasegawa, Bruce H.Medical Physics (2004), 31 (9), 2680-2686CODEN: MPHYA6; ISSN:0094-2405. (American Institute of Physics)Calcns. of radiation dose are important in assessing the medical and biol. implications of ionizing radiation in medical imaging techniques such as SPECT and PET. In contrast, radiation dose ests. of SPECT and PET imaging of small animals are not very well established. For that reason we have estd. the whole-body radiation dose to mice and rats for isotopes such as 18F, 99mTc, 201Tl, 111In, 123I, and 125I that are used commonly for small animal imaging. We have approximated mouse and rat bodies with uniform soft tissue equiv. ellipsoids. The mouse and rat sized ellipsoids had a mass of 30 g and 300 g, resp., and a ratio of the principal axes of 1:1:4 and 0.7:1:4. The absorbed fractions for various photon energies have been calcd. using the Monte Carlo software package MCNP. Using these values, we then calcd. MIRD S-values for two geometries that model the distribution of activity in the animal body: (a) a central point source and (b) a homogeneously distributed source, and compared these values against S-value calcns. for small ellipsoids tabulated in MIRD Pamphlet 8 to validate our results. Finally we calcd. the radiation dose taking into account the biol. half-life of the radiopharmaceuticals and the amt. of activity administered. Our calcns. produced S-values between 1.06×10-13 Gy/Bq s and 2.77×10-13 Gy/Bq s for SPECT agents, and 15.0×10-13 Gy/Bq s for the PET agent 18F, assuming mouse sized ellipsoids with uniform source distribution. The S-values for a central point source in an ellipsoid are about 10% higher than the values obtained for the uniform source distribution. Furthermore, the S-values for mouse sized ellipsoids are approx. 10 times higher than for the rat sized ellipsoids reflecting the difference in mass. We reviewed published data to obtain administered radioactivity and residence times for small animal imaging. From these values and our computed S-values we estd. that the whole body dose in small animals ranges between 6 cGy and 90 cGy for mice and between about 1 cGy and 27 cGy for rats. The whole body dose in small animal imaging can be very high in comparison to the LD to mice (LD50/30≈7 Gy). For this reason the dose in small animal imaging should be monitored carefully and the administered activity should be kept to a min. These results also underscore the need of further development of instrumentation that improves detection efficiency and reduces radiation dose in small animal imaging.
- 23Dong, F.; Du, J.; Miao, C.; Jia, L.; Li, W.; Wang, M.; Zheng, Q.-H.; Xu, Z. Radiosynthesis of carbon-11 labeled PDE5 inhibitors as new potential PET radiotracers for imaging of Alzheimer’s disease. Appl. Radiat. Isot. 2019, 154, 108873, DOI: 10.1016/j.apradiso.2019.108873[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1GktL7M&md5=c30f25f6570a5233a5343c4efb19c163Radiosynthesis of carbon-11 labeled PDE5 inhibitors as new potential PET radiotracers for imaging of Alzheimer's diseaseDong, Fugui; Du, Jie; Miao, Caihong; Jia, Limeng; Li, Wei; Wang, Min; Zheng, Qi-Huang; Xu, ZhidongApplied Radiation and Isotopes (2019), 154 (), 108873CODEN: ARISEF; ISSN:0969-8043. (Elsevier Ltd.)To develop PET tracers for imaging of Alzheimer's disease, new carbon-11 labeled potent and selective PDE5 inhibitors have been synthesized. The ref. stds. (5) and (12), and their corresponding desmethylated precursors (6) and (13) were synthesized from Me 2-amino-5-bromobenzoate and (4-methoxyphenyl)methanamine in multiple steps with 2%, 1%, 1% and 0.2% overall chem. yield, resp. The radiotracers ([11C]5) and ([11C]12) were prepd. from their corresponding precursors 6 and 13 with [11C]CH3OTf through O-11C-methylation and isolated by HPLC combined with SPE in 40-50% radiochem. yield, based on [11C]CO2 and decay cor. to EOB. The radiochem. purity was >99%, and the molar activity (Am) at EOB was in a range of 370-740 GBq/μmol.
- 24Gillings, N.; Todde, S.; Behe, M.; Decristoforo, C.; Elsinga, P.; Ferrari, V.; Hjelstuen, O.; Peitl, P. K.; Koziorowski, J.; Laverman, P.; Mindt, T. L.; Ocak, M.; Patt, M. EANM guideline on the validation of analytical methods for radiopharmaceuticals. EJNMMI Radiopharmacy and Chemistry. 2020, 5, 7, DOI: 10.1186/s41181-019-0086-z[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB387hsFamsA%253D%253D&md5=7314214c730ee0cf30686a6ddf9d3fd7EANM guideline on the validation of analytical methods for radiopharmaceuticalsGillings Nic; Todde Sergio; Behe Martin; Decristoforo Clemens; Elsinga Philip; Ferrari Valentina; Hjelstuen Olaug; Peitl Petra Kolenc; Koziorowski Jacek; Laverman Peter; Mindt Thomas L; Ocak Meltem; Patt MarianneEJNMMI radiopharmacy and chemistry (2020), 5 (1), 7 ISSN:.BACKGROUND: To fulfil good manufacturing requirements, analytical methods for the analysis of pharmaceuticals for human and vetinary use must be validated. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has published guidance documents on the requirements for such validation activities and these have been adopted by the European Medicines Agency, The U.S. Food and Drug Administration (FDA) and other regulatory bodies. These guidance documents do not, however, fully address all the specific tests required for the analysis of radiopharmaceuticals. This guideline attempts to rectify this shortcoming, by recommending approaches to validate such methods. RESULTS: Recommedations for the validation of analytical methods which are specific for radiopharmaceutials are presented in this guideline, along with two practical examples. CONCLUSIONS: In order to comply with good manufacturing practice, analytical methods for radiopharmaceuticals for human use should be validated.
- 25Li, S.; Schmitz, A.; Lee, H.; Mach, R. H. Automation of the radiosynthesis of six different 18F-labeled radiotracers on the allinone. EJNMMI Radiopharmacy and Chemistry. 2017, 1, 15, DOI: 10.1186/s41181-016-0018-0[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mnjs1egug%253D%253D&md5=bec3c23b749ff45e1056e5801c2adaa5Automation of the Radiosynthesis of Six Different (18)F-labeled radiotracers on the AllinOneLi Shihong; Schmitz Alexander; Lee Hsiaoju; Mach Robert HEJNMMI radiopharmacy and chemistry (2017), 1 (1), 15 ISSN:.Background: Fast implementation of positron emission tomography (PET) into clinical and preclinical studies highly demands automated synthesis for the preparation of PET radiopharmaceuticals in a safe and reproducible manner. The aim of this study was to develop automated synthesis methods for these six (18)F-labeled radiopharmaceuticals produced on a routine basis at the University of Pennsylvania using the AllinOne synthesis module. Results: The development of automated syntheses with varying complexity was accomplished including HPLC purification, SPE procedures and final formulation with sterile filtration. The six radiopharmaceuticals were obtained in high yield and high specific activity with full automation on the AllinOne synthesis module under current good manufacturing practice (cGMP) guidelines. Conclusion: The study demonstrates the versatility of this synthesis module for the preparation of a wide variety of (18)F-labeled radiopharmaceuticals for PET imaging studies.
- 26Mehmood, Y. What Is Limulus Amebocyte Lysate (LAL) and Its Applicability in Endotoxin Quantification of Pharma Products. In Growing and Handling of Bacterial Cultures; Mishra, M., Ed.; IntechOpen: 2019.
- 27Tu, Z.; Mach, R. H. C-11 radiochemistry in cancer imaging applications. Curr. Top. Med. Chem. 2010, 10, 1060– 1095, DOI: 10.2174/156802610791384261[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovFaqs7o%253D&md5=75c9b8aedd01b1f8b7917c30c77f6e63C-11 radiochemistry in cancer imaging applicationsTu, Z.; Mach, R. H.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (11), 1060-1095CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. Carbon-11 (C-11) radiotracers are widely used for the early diagnosis of cancer, monitoring therapeutic response to cancer treatment, and pharmacokinetic investigations of anticancer drugs. PET imaging permits non-invasive monitoring of metabolic processes and mol. targets, while carbon-11 radiotracers allow a "hot for cold" substitution of biol. active mols. Advances in org. synthetic chem. and radiochem. as well as improved automated techniques for radiosynthesis have encouraged investigators in developing carbon-11 tracers for use in oncol. imaging studies. The short half-life of carbon-11 (20.38 min) creates special challenges for the synthesis of C-11 labeled tracers; these include the challenges of synthesizing C-11 target compds. with high radiochem. yield, high radiochem. purity and high specific activity in a short time and on a very small scale. The optimization of conditions for making a carbon-11 tracer include the late introduction of the C-11 isotope, the rapid formation and purifn. of the target compd., and the use of automated systems to afford a high yield of the target compd. in a short time. In this review paper, we first briefly introduce some basic principles of PET imaging of cancer; we then discuss principles of carbon-11 radiochem., focus on specific advances in radiochem., and describe the synthesis of C-11 radiopharmaceuticals developed for cancer imaging. The carbon-11 radiochem. approaches described include the N,O, and S-alkylations of [11C]methyl iodide/[11C]methyl triflate and analogs of [11C]methyl iodide and their applications for making carbon-11 tracers; we then address recent advances in exploring a transmetallic complex mediated [11C]carbonyl reaction for oncol. targets.
- 28Luurtsema, G.; Verbeek, J.; Lubberink, M.; Lammertsma, A. A.; Dierckx, R.; Elsinga, P.; Windhorst, A. D.; van Waarde, A. Carbon-11 labeled tracers for in vivo imaging of P- glycoprotein function: Kinetics, advantages and disadvantages. Curr. Top. Med. Chem. 2010, 10, 1820– 1833, DOI: 10.2174/156802610792928013[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cfkslKnsw%253D%253D&md5=ccf0b321e7329db173e793590542075aCarbon-11 labeled tracers for in vivo imaging P-glycoprotein function: kinetics, advantages and disadvantagesLuurtsema G; Verbeek G L; Lubberink M; Lammertsma A A; Dierckx R; Elsinga P; Windhorst A D; van Waarde ACurrent topics in medicinal chemistry (2010), 10 (17), 1820-33 ISSN:.P-glycoprotein (P-gp) is a drug efflux transporter with broad substrate specificity localized in the blood-brain barrier and in several peripheral organs. In order to understand the role of P-gp in physiological and patho-physiological conditions, several carbon-11 labelled P-gp tracers have been developed and validated. This review provides an overview of the spectrum of radiopharmaceuticals that is available for this purpose. A short overview of the physiology of the blood-brain barrier in health and disease is also provided. Tracer kinetic modelling for quantitative analysis of P-gp function and expression is highlighted, and the advantages and disadvantages of the various tracers are discussed.
- 29Dahl, K.; Halldin, C.; Schou, M. New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals. Clinical and Translational Imaging. 2017, 5, 275– 289, DOI: 10.1007/s40336-017-0223-1[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnmsFGmtg%253D%253D&md5=35efea104c0af2ef8e9b45c4826a47b5New methodologies for the preparation of carbon-11 labeled radiopharmaceuticalsDahl Kenneth; Halldin Christer; Schou Magnus; Schou MagnusClinical and translational imaging (2017), 5 (3), 275-289 ISSN:2281-5872.PURPOSE: This short review aims to cover the more recent and promising developments of carbon-11 ((11)C) labeling radiochemistry and its utility in the production of novel radiopharmaceuticals, with special emphasis on methods that have the greatest potential to be translated for clinical positron emission tomography (PET) imaging. METHODS: A survey of the literature was undertaken to identify articles focusing on methodological development in (11)C chemistry and their use within novel radiopharmaceutical preparation. However, since (11)C-labeling chemistry is such a narrow field of research, no systematic literature search was therefore feasible. The survey was further restricted to a specific timeframe (2000-2016) and articles in English. RESULTS: From the literature, it is clear that the majority of (11)C-labeled radiopharmaceuticals prepared for clinical PET studies have been radiolabeled using the standard heteroatom methylation reaction. However, a number of methodologies have been developed in recent years, both from a technical and chemical point of view. Amongst these, two protocols may have the greatest potential to be widely adapted for the preparation of (11)C-radiopharmaceuticals in a clinical setting. First, a novel method for the direct formation of (11)C-labeled carbonyl groups, where organic bases are utilized as [(11)C]carbon dioxide-fixation agents. The second method of clinical importance is a low-pressure (11)C-carbonylation technique that utilizes solvable xenon gas to effectively transfer and react [(11)C]carbon monoxide in a sealed reaction vessel. Both methods appear to be general and provide simple paths to (11)C-labeled products. CONCLUSION: Radiochemistry is the foundation of PET imaging which relies on the administration of a radiopharmaceutical. The demand for new radiopharmaceuticals for clinical PET imaging is increasing, and (11)C-radiopharmaceuticals are especially important within clinical research and drug development. This review gives a comprehensive overview of the most noteworthy (11)C-labeling methods with clinical relevance to the field of PET radiochemistry.
- 30Rami-Mark, C.; Ungersboeck, J.; Haeusler, D.; Nics, L.; Philippe, C.; Mitterhauser, M.; Willeit, M.; Lanzenberger, R.; Karanikas, G.; Wadsak, W. Reliable set-up for in-loop 11C- carboxylations using Grignard reactions for the preparation of [carbonyl-11C]WAY- 100635 and [11C]-(+)-PHNO. Appl. Radiat. Isot. 2013, 82, 75– 80, DOI: 10.1016/j.apradiso.2013.07.023[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslKqsbbF&md5=f0c93e325715abc0db09121bfe7ecb05Reliable set-up for in-loop 11C-carboxylations using Grignard reactions for the preparation of [carbonyl-11C]WAY-100635 and [11C]-(+)-PHNORami-Mark, Christina; Ungersboeck, Johanna; Haeusler, Daniela; Nics, Lukas; Philippe, Cecile; Mitterhauser, Markus; Willeit, Matthaeus; Lanzenberger, Rupert; Karanikas, Georgios; Wadsak, WolfgangApplied Radiation and Isotopes (2013), 82 (), 75-80CODEN: ARISEF; ISSN:0969-8043. (Elsevier Ltd.)Aim of this work was the implementation of a generalized in-loop synthesis for 11C-carboxylations and subsequent 11C-acylations on the TRACERlab FxC Pro platform. The set-up was tested using [carbonyl-11C]WAY-100635 and, for the first time, [11C]-(+)-PHNO. Its general applicability could be demonstrated and both [carbonyl-11C]WAY-100635 and [11C]-(+)-PHNO were prepd. with high reliability and satisfying outcome.
- 31Rotstein, B. H.; Liang, S. H.; Holland, J. P.; Collier, T. L.; Hooker, J. M.; Wilson, A. A.; Vasdev, N. 11CO2 fixation: A renaissance in PET radiochemistry. Chem. Commun. 2013, 49, 5621, DOI: 10.1039/c3cc42236d[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosVemsbo%253D&md5=555cd1c94c0e870cf268ff5db0578c0c11CO2 fixation: a renaissance in PET radiochemistryRotstein, Benjamin H.; Liang, Steven H.; Holland, Jason P.; Collier, Thomas Lee; Hooker, Jacob M.; Wilson, Alan A.; Vasdev, NeilChemical Communications (Cambridge, United Kingdom) (2013), 49 (50), 5621-5629CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Carbon-11 labeled carbon dioxide is the cyclotron-generated feedstock reagent for most positron emission tomog. (PET) tracers using this radionuclide. Most carbon-11 labels, however, are installed using deriv. reagents generated from [11C]CO2. In recent years, [11C]CO2 has seen a revival in applications for the direct incorporation of carbon-11 into functional groups such as ureas, carbamates, oxazolidinones, carboxylic acids, esters, and amides. This review summarizes classical [11C]CO2 fixation strategies using organometallic reagents and then focuses on newly developed methods that employ strong org. bases to reversibly capture [11C]CO2 into soln., thereby enabling highly functionalized labeled compds. to be prepd. Labeled compds. and radiopharmaceuticals that have been translated to the clinic are highlighted.
- 32Hooker, J. M.; Reibel, A. T.; Hill, S. M.; Schueller, M. J.; Fowler, J. S. One-pot, direct incorporation of [11C]CO2 into carbamates. Angew. Chem., Int. Ed. 2009, 48, 3482– 3485, DOI: 10.1002/anie.200900112[Crossref], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXltFGhsL8%253D&md5=3710164e039643639811d7999396229dOne-Pot, Direct Incorporation of [11C]CO2 into CarbamatesHooker, Jacob M.; Reibel, Achim T.; Hill, Sidney M.; Schueller, Michael J.; Fowler, Joanna S.Angewandte Chemie, International Edition (2009), 48 (19), 3482-3485, S3482/1-S3482/10CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An operationally simple and mild reaction based on the direct fixation of 11CO2 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) has been developed for the synthesis of 11C-labeled carbamates at 75 °C within 10 min in radiochem. yields above 70 % (see scheme). This strategy should be immediately useful for the construction of new radiotracers for positron emission tomog. and other applications.
- 33Wilson, A. A.; Garcia, A.; Houle, S.; Vasdev, N. Direct fixation of [11C]-CO2 by amines: Formation of [11C-carbonyl]-methylcarbamates. Org. Biomol. Chem. 2010, 8, 428– 432, DOI: 10.1039/B916419G[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1Sqs7nK&md5=9d718725aeb709e694b43db9c4d0edb9Direct fixation of [11C]-CO2 by amines: formation of [11C-carbonyl]-methylcarbamatesWilson, Alan A.; Garcia, Armando; Houle, Sylvain; Vasdev, NeilOrganic & Biomolecular Chemistry (2010), 8 (2), 428-432CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)[11C-Carbonyl]-methylcarbamates can be synthesized directly from [11C]-CO2 and primary or secondary amines in a one-pot, two-step reaction. The use of either diazabicyclo[5.4.0]undec-7-ene (DBU) or 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) enables efficient trapping of [11C]-CO2 in small vols. of DMF as [11C]-carbamate salts. Subsequent reaction with a variety of methylating agents rapidly generates the desired [11C-carbonyl]-methylcarbamates in high radiochem. yields. The usefulness of the method is illustrated by the efficient radiosynthesis of a kappa opioid receptor imaging radiotracer, [11C]-GR103545, useful in positron emission tomog.
- 34Taddei, C.; Gee, A. D. Recent progress in [11C]carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) chemistry. J. Labelled Compd. Radiopharm. 2018, 61, 237– 251, DOI: 10.1002/jlcr.3596[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1Wnu7s%253D&md5=85da8695e14ceabc45fa7eeaf5895c47Recent progress in [11C]carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) chemistryTaddei, Carlotta; Gee, Antony D.Journal of Labelled Compounds and Radiopharmaceuticals (2018), 61 (3), 237-251CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)[11C]Carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) are 2 attractive precursors for labeling the carbonyl position (CO) in a vast range of functionalised mols. (eg, ureas, amides, and carboxylic acids). The development of radiosynthetic methods to produce functionalised 11C-labeled compds. is required to enhance the radiotracers available for positron emission tomog., mol., and medical imaging applications. Following a brief summary of secondary 11C-precursor prodn. and uses, the review focuses on recent progress with direct 11C-carboxylation routes with [11C]CO2 and 11C-carbonylation with [11C]CO. Novel approaches to generate [11C]CO using CO-releasing mols. (CO-RMs), such as silacarboxylic acids and disilanes, applied to radiochem. are described and compared with std. [11C]CO prodn. methods. These innovative [11C]CO synthesis strategies represent efficient and reliable [11C]CO prodn. processes, enabling the widespread use of [11C]CO chem. within the wider radiochem. community.
- 35Eriksson, J.; Antoni, G.; Långström, B.; Itsenko, O. The development of 11C- carbonylation chemistry: A systematic view. Nuclear Medicine and Biology 2020, DOI: 10.1016/j.nucmedbio.2020.02.005
- 36Taddei, C.; Pike, V. W. [11C]Carbon monoxide: Advances in production and application to PET radiotracer development over the past 15 years. EJNMMI Radiopharmacy and Chemistry. 2019, 4, 25, DOI: 10.1186/s41181-019-0073-4[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MjisVCltQ%253D%253D&md5=fab5f957b3e21fb707b66231df502116(11)C]Carbon monoxide: advances in production and application to PET radiotracer development over the past 15 yearsTaddei Carlotta; Pike Victor WEJNMMI radiopharmacy and chemistry (2019), 4 (1), 25 ISSN:.[(11)C]Carbon monoxide is an appealing synthon for introducing carbon-11 at a carbonyl position (C=O) in a wide variety of chemotypes (e.g., amides, ketones, acids, esters, and ureas). The prevalence of the carbonyl group in drug molecules and the present-day broad versatility of carbonylation reactions have led to an upsurge in the production of this synthon and in its application to PET radiotracer development. This review focuses on the major advances of the past 15 years.
- 37Hooker, J. M.; Schönberger, M.; Schieferstein, H.; Fowler, J. S. A simple, rapid method for the preparation of [11C]formaldehyde. Angew. Chem., Int. Ed. 2008, 47, 5989– 5992, DOI: 10.1002/anie.200800991[Crossref], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpsleitL8%253D&md5=d03c476e24a5ac45417b508b5308b4cdA simple, rapid method for the preparation of [11C]formaldehydeHooker, Jacob M.; Schoenberger, Matthias; Shchieferstein, Hanno; Fowler, Joanna S.Angewandte Chemie, International Edition (2008), 47 (32), 5989-5992, S5989/1-S5989/10CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A PET project: A powerful reagent for the synthesis of positron-emitting imaging mols.-[11C]formaldehyde-is accessible from [11C]methyl iodide and trimethylamine N-oxide (TMAO) in high yields and under mild conditions. Easy access to [11C]formaldehyde expands the scope of the carbon-11 toolbox and will lead to new reaction methodol. and imaging compds.
- 38Luthra, S. K.; Pike, V. W.; Brady, F. Preparation of some NCA [1–11C]acid chlorides as labelling agents. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1990, 41, 471– 476, DOI: 10.1016/0883-2889(90)90007-4
- 39McCarron, J. A.; Turton, D. R.; Pike, V. W.; Poole, K. G. Remotely-controlled production of the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635, via 11C- carboxylation of an immobilized Grignard reagent. J. Labelled Compd. Radiopharm. 1996, 38, 941– 953, DOI: 10.1002/(SICI)1099-1344(199610)38:10<941::AID-JLCR906>3.0.CO;2-Y[Crossref], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xmt1Kqsbw%253D&md5=9c802c13824bf3933769550ad0146b68Remotely-controlled production of the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635McCarron, Julie A.; Turton, David R.; Pike, Victor W.; Poole, Keith G.Journal of Labelled Compounds & Radiopharmaceuticals (1996), 38 (10), 941-953CODEN: JLCRD4; ISSN:0362-4803. (Wiley)N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide labeled in the carbonyl position with 11C (I), an effective radioligand for the study of 5-HT1A receptors in human brain by positron emission tomog., was prepd. Thus, cyclohexylmagnesium chloride coated on the inner surface of a narrow polypropylene tube was carboxylated by cyclotron-produced 11CO2 followed by passage of SOCl2 to convert the trapped radioactive adduct and to release the labeling agent into a vial contg. 1-(2-methoxyphenyl)-4-[2-(2-pyridylamino)ethyl]piperazine. The procedure was readily adapted for operation in a shielded hot-cell with remote control for radiation safety. The remotely-controlled radiosynthesis takes 45 min and gives high radioactivities (2.96-5.92 GBq) of I in >99% radiochem. purity and high specific radioactivity (av. 192 GBq/μmol).
- 40Marazano, C.; Maziere, M.; Berger, G.; Comar, D. Synthesis of methyl iodide-11C and formaldehyde-11C. Int. J. Appl. Radiat. Isot. 1977, 28, 49– 52, DOI: 10.1016/0020-708X(77)90159-4[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXktFyntrg%253D&md5=70689828769597881ebba801d609cd29Synthesis of methyl iodide-11C and formaldehyde-11CMarazano, Christian; Maziere, Mariannick; Berger, Gerard; Comar, DominiqueInternational Journal of Applied Radiation and Isotopes (1977), 28 (1-2), 49-52CODEN: IJARAY; ISSN:0020-708X.A fast 2-stage method of prepg. H211CO and 11CH3I is described. 11CO2 was reduced to 11CH3OH by LiAlH4 in THF, this product leading to H211CO by oxidn. on Ag catalyst or to 11CH3I by reaction with HI. It is easy to methylate certain chem. groups by use of these 2 mols. and the method was used to label substance of biol. interest for research in vivo. The sp. activity at the moment of use is 20-30 mCi/μmol, which indicates a high isotopic dilution.
- 41Joshi, R. K.; Goud, N. S.; Nagaraj, C.; Kumar, D.; R, G.; Rao, N. P.; Dhawan, A.; Bhattacharya, A.; Mangalore, S.; Bharath, R. D.; Kumar, P. Radiosynthesis Challenges of 11C and 18F-Labeled Radiotracers in the FX2C/N Tracerlab and Their Validation through PET-MR Imaging. Appl. Radiat. Isot. 2021, 168, 109486, DOI: 10.1016/j.apradiso.2020.109486[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1Gqsb3K&md5=2ccc954fd055aa8488e5fff5514e4eb9Radiosynthesis challenges of 11C and 18F-labeled radiotracers in the FX2C/N tracerlab and their validation through PET-MR imagingJoshi, Raman Kumar; Goud, Nerella Sridhar; Nagaraj, Chandana; Kumar, Dinesh; R, Gopinath; Rao, Naren P.; Dhawan, Anmol; Bhattacharya, Ahana; Mangalore, Sandhya; Bharath, Rose Dawn; Kumar, PardeepApplied Radiation and Isotopes (2021), 168 (), 109486CODEN: ARISEF; ISSN:0969-8043. (Elsevier Ltd.)Glucose is the renowned source of the energy for the cancer growth, that's the reason for [18F]FDG success and make it widely used radiotracer. Though [18F]FDG has its own inherent limitations therefore many tracers have been developed to target specific receptors, and other metabolic routes. We have used FX2C and FX2N Tracerlab modules for the synthesis of the [11C]methionine, [18F]choline and [18F]fluorodopa via nucleophilic pathway in FX2C/N module. [11C]methionine was standardized in FX2C module using two different precursors, and purified using C18 cartridge based technique. [18F]methylcholine was synthesized using dimethylaminoethanol precursor and purified using cartridge-based method. [18F]fluorodopa was synthesized using nucleophilic precursor and purified using in-built preparative HPLC on FX2N module. All radioactive intermediates and chem. impurities were evaluated by anal. HPLC. The radiochem. purity of D and L-[11C]methionine were 4.6 ± 3.2% and 95.4 ± 3.6% while other chem. impurities were less than prescribed limits with yield of 20 ± 5%. [18F]fluoromethylcholine was prepd. with high radiochem. purity of 97.3 ± 2.6% with yield of 8 ± 3%. [18F]fluorodopa was synthesized with high radiochem. purity of 95.8 ± 1.4% with 15 ± 3% yield. The adaptation of [18F]fluorodopa synthesis to FX2N module via designing synthesis sequence and purified through online HPLC has provided high radiochem. purity. PET-MR imaging was done using these tracers which have validated the synthesis and their availability for future clin. applications.
- 42Schoeps, K.-O.; Långström, B.; Stone-Elander, S.; Halldin, C. Synthesis of [1–11C]d- glucose and [1–11C]d-mannose from on-line produced [11C]nitromethane. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1991, 42, 877– 883, DOI: 10.1016/0883-2889(91)90228-S[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK38%252FktV2msQ%253D%253D&md5=9f6284b2c531c31466cd8e07e4d22f75Synthesis of [1-11C]D-glucose and [1-11C]D-mannose from on-line produced [11C]nitromethaneSchoeps K O; Langstrom B; Stone-Elander S; Halldin CInternational journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes (1991), 42 (9), 877-83 ISSN:0883-2889.A method for the preparation of [1-11C]D-glucose (III) and [1-11C] D-mannose (IV) from [11C] nitromethane is described. [11C]Nitromethane was produced using the on-line method from [11C]methyl iodide. The condensation of no-carrier-added or carrier-added [11C]nitromethane with D-arabinose to form the intermediate epimeric [1-11C]D-nitro alcohols (I and II) was investigated under various conditions. Compounds I and II were converted to III and IV by the classical Nef reaction with IV as the major product [(IV)/(III) = 3/1-4/1]. The isolated radiochemical yield of III and IV was 25-30% (based on [11C]nitromethane and decay-corrected) and 14-17% (EOB) with a total synthesis time of 50 min, including HPLC-purification. Compounds III and IV were isolated using semi-preparative HPLC and the radiochemical purity was greater than 97%. In a typical run, 1.5-2.0 mCi of III and 6-8 mCi of IV could be isolated (starting from 70-90 mCi [11C]nitromethane).
- 43Kadirvel, M.; Cardoso, D.; Freeman, S.; Brown, G. Radiosynthesis and reactivity of N- [11C]methyl carbamoylimidazole. J. Radioanal. Nucl. Chem. 2018, 317, 977– 984, DOI: 10.1007/s10967-018-5948-4[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFOmsbbI&md5=90fd0864da52030388eada1898fcab0eRadiosynthesis and reactivity of N-[11C]methyl carbamoylimidazoleKadirvel, Manikandan; Cardoso, Deborah; Freeman, Sally; Brown, GavinJournal of Radioanalytical and Nuclear Chemistry (2018), 317 (2), 977-984CODEN: JRNCDM; ISSN:0236-5731. (Springer)A new chem. route for synthesis of N-Me carbamoylimidazole from Me iodide was developed as an safe alternative to Me isocyanate for carbamoylation reaction and applied this to the synthesis of N-[11C]methyl carbamoylimidazole as a new [11C]synthon to radiolabel biomols. for PET imaging research. N-[11C]methyl carbamoylimidazole was prepd. from [11C]methyl iodide in 70-74% radiochem. yield (decay cor.) and was used in-situ for further reaction without purifn. The reactivity of N-[11C]methyl carbamoylimidazole was demonstrated in a series of [11C]carbamoylation reactions.
- 44Jewett, D. M. A simple synthesis of [11C]methyl triflate. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1992, 43, 1383– 1385, DOI: 10.1016/0883-2889(92)90012-4[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s%252FosVGjsw%253D%253D&md5=145672eefe5e62481fa86b1a5d0abfc4A simple synthesis of [11C]methyl triflateJewett D MInternational journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes (1992), 43 (11), 1383-5 ISSN:0883-2889.[11C]Methyl triflate ([11C]methyl trifluoromethanesulfonate) was formed in high yield when [11C]methyl iodide in a nitrogen carrier was passed at 200 degrees C through a column containing graphitized carbon impregnated with 50% by weight of silver triflate.
- 45Haywood, T.; Kealey, S.; Sánchez-Cabezas, S.; Hall, J. J.; Allott, L.; Smith, G.; Plisson, C.; Miller, P. W. Carbon-11 radiolabelling of organosulfur compounds: 11C synthesis of the progesterone receptor agonist tanaproget. Chem. - Eur. J. 2015, 21, 9034– 9038, DOI: 10.1002/chem.201501089[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotlCqtLY%253D&md5=5c84cfaff7732ef34652770bea10e29bCarbon-11 Radiolabelling of Organosulfur Compounds: 11C Synthesis of the Progesterone Receptor Agonist TanaprogetHaywood, Tom; Kealey, Steven; Sanchez-Cabezas, Santiago; Hall, James J.; Allott, Louis; Smith, Graham; Plisson, Christophe; Miller, Philip W.Chemistry - A European Journal (2015), 21 (25), 9034-9038CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Herein, a new 11C radiolabelling strategy for the fast and efficient synthesis of thioureas and related derivs. using the novel synthon, 11CS2, is reported. This approach has enabled the facile labeling of a potent progesterone receptor (PR) agonist, [11C]Tanaproget, by the intramol. reaction of the acyclic aminohydroxyl precursor with 11CS2, which has potential applications as a positron emission tomog. radioligand for cancer imaging.
- 46Shao, X.; Rodnick, M. E.; Brooks, A. F.; Scott, P. J. H. Synthesis and Applications of [11C]Hydrogen Cyanide. In Radiochemical Syntheses; Scott, P. J. H., Ed.; John Wiley & Sons, Inc: Hoboken, NJ, 2015; pp 233– 240.
- 47Haskali, M. B.; Pike, V. W. [11C]fluoroform, a breakthrough for versatile labeling of PET radiotracer trifluoromethyl groups in high molar activity. Chem. - Eur. J. 2017, 23, 8156– 8160, DOI: 10.1002/chem.201701701[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvVCqtL4%253D&md5=1097b58d7010f9d83232a988621af5bd[11C]Fluoroform, a Breakthrough for Versatile Labeling of PET Radiotracer Trifluoromethyl Groups in High Molar ActivityHaskali, Mohammad B.; Pike, Victor W.Chemistry - A European Journal (2017), 23 (34), 8156-8160CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Positron-emission tomog. (PET) is an immensely important imaging modality in biomedical research and drug development but must use selective radiotracers to achieve biochem. specificity. Such radiotracers are usually labeled with carbon-11 (t1/2=20 min) or fluorine-18 (t1/2=110 min), but these are only available from cyclotrons in a few simple chem. forms. [18F]Fluoroform has emerged for labeling tracers in trifluoromethyl groups but is severely limited in utility by low radioactivity per mass (low molar activity). Here, the synthesis of [11C]fluoroform is described, based on CoF3-mediated fluorination of cyclotron-produced [11C]methane. This process is efficient and repetitively reliable. [11C]Fluoroform shows versatility for labeling small mols. in very high molar activity (>200 GBq μmol-1), far exceeding that possible by using [18F]fluoroform. Therefore, [11C]fluoroform represents a major breakthrough for labeling prospective PET tracers in trifluoromethyl groups at high molar activity.
- 48Roeda, D.; Dolle, F. [11C]Phosgene: A versatile reagent for radioactive carbonyl insertion into medicinal radiotracers for positron emission tomography. Curr. Top. Med. Chem. 2010, 10, 1680– 1700, DOI: 10.2174/156802610793176710[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1ahtrrO&md5=197a317eeac308494cb0bc65b11d74fb[11C]Phosgene, a versatile reagent for radioactive carbonyl insertion into medicinal radiotracers for positron emission tomographyRoeda, Dirk; Dolle, FredericCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (16), 1680-1700CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. [11C]phosgene was playing a relatively modest but continuous and manifest role all along the history of radiochem. for Positron Emission Tomog. It acts as a radiolabeling agent through carbonyl insertion, usually between heteroatoms, and benefits from a high chem. reactivity allowing for short reaction times. This review gave an overview of this radiochem. from its beginning until the present day. After drawing up the inventory of the various ways of its prodn., the reactions in which it was employed and the labeled products that were synthesized with it are cataloged. This comprises the reactions of [11C]phosgene with primary, secondary and tertiary amines to labeled isocyanates and carbamoyl chlorides, which serve as intermediates for sym. and unsym. [11C]ureas and [11C]carbamates, reactions with alcs. leading to labeled carbamates and carbonates via [11C]chloroformates, cyclization reactions to heterocycles and the radiochem. of the secondary radiolabeling agents [11C]urea and diethyl- or di-Me [11C]carbonate. Apart from this already vast field of chem. possibilities there should be room for extension of the use of [11C]phosgene to other chem., notably that of C-11C bond formation.
- 49Landais, P.; Crouzel, C. A new synthesis of carbon-11 labelled phosgene. International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes. 1987, 38, 297– 300, DOI: 10.1016/0883-2889(87)90042-6
- 50Szlosek-Pinaud, M.; Allard, M.; Fouquet, E.; James, D. State of art in 11C labelled radiotracers synthesis. Curr. Med. Chem. 2008, 15, 235– 277, DOI: 10.2174/092986708783497292[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsVyisrc%253D&md5=3373ad7cc94dfe53fcaf6114b0ddaa63State of art in 11C labelled radiotracers synthesisAllard, M.; Fouquet, E.; James, D.; Szlosek-Pinaud, M.Current Medicinal Chemistry (2008), 15 (3), 235-277CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Positron Emission Tomog. has become a powerful scientific and clin. tool probing biochem. processes in the human body. Their clin. applications have proven to be vital in the evaluation and diagnosis of diseases. This is due, in large part, to advances in instrumentation and synthetic chem. Carbon-11 is a valuable radionuclide in PET as it virtually permits the synthesis of radiolabeled versions of any compd. of interest. The syntheses with carbon-11 present several features: limited no. of labeled precursors, sub-micromolar amts. of the starting materials, and a need for the introduction of the radioisotope as late as possible in the synthesis. All of these reasons have restricted complex radiosyntheses. The short half-life of carbon-11 (20.4 min) requires the rapid prepn. and purifn. of carbon-11 labeled mols. Those have to be carried out immediately before use from cyclotron produced precursors ([11C]CO2, [11C]CO, [11C]CH4) or reagents rapidly prepd. from them ([11C]CH3I, [11C]COCI2, [11C]HCN). As a consequence carbon-11 has been underused compared to fluorine-18. However, because of the increasing mol. complexity and diversity of biol. active compds., there is a need for new methodologies giving access in short time and high yield to radioactive 11C-probes. The aim of this review is to emphasize the methodologies used in this field and to give a comprehensive overview of the numerous advances, which occurred over the past decade. In addn., for each labeling technique or reaction reported, a special attention has been brought to classify the applications in function of the targeted medical domain.
- 51Wuest, F.; Berndt, M.; Kniess, T. Carbon-11 Labeling Chemistry Based upon [11C]Methyl Iodide. In PET Chemistry; Schubiger, P. A., Lehmann, L., Friebe, M., Eds.; Springer: Berlin Heidelberg, 2007; Vol. 64, pp 183– 213.
- 52Pekošak, A.; Filp, U.; Poot, A. J.; Windhorst, A. D. From carbon-11-labeled amino acids to peptides in positron emission tomography: The synthesis and clinical application. Molecular Imaging and Biology. 2018, 20, 510– 532, DOI: 10.1007/s11307-018-1163-5[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlantLY%253D&md5=60ce7e563ca3435241808637189e242fFrom Carbon-11-Labeled Amino Acids to Peptides in Positron Emission Tomography: the Synthesis and Clinical ApplicationPekosak, Aleksandra; Filp, Ulrike; Poot, Alex J.; Windhorst, Albert D.Molecular Imaging and Biology (2018), 20 (4), 510-532CODEN: MIBOCZ; ISSN:1860-2002. (Springer)A review. Radiolabeled amino acids, their derivs. and peptides have a broad scope of application and can be used as receptor ligands, as well as enzyme substrates for many different diseases as radiopharmaceutical tracers. Over the past few decades, the application of mol. imaging techniques such as positron emission tomog. (PET) has gained considerable importance and significance in diagnosis in today's advanced health care. Next to that, the availability of cyclotrons and state-of-the-art radiochem. facilities has progressed the prodn. of imaging agents enabling the prepn. of many versatile PET radiotracers. Due to many favorable characteristics of radiolabeled amino acids and peptides, they can be used for tumor staging and monitoring the progress of therapy success, while arom. amino acids can be employed as PET tracer to study neurol. disorders. This review provides a comprehensive overview of radiosynthetic and enzymic approaches towards carbon-11 amino acids, their analogs and peptides, with focus on stereoselective reactions, and reflects upon their clin. application.
- 53Antoni, G.; Kihlberg, T.; Långström, B. 11C: Labeling Chemistry and Labeled Compounds. In Handbook of Nuclear Chemistry; Vértes, A., Nagy, S., Klencsár, Z., Lovas, R. G., Rösch, F., Eds.; Springer US: Boston, MA, 2011; pp 1977– 2019.
- 54Correa, A.; Martín, R. Metal-catalyzed carboxylation of organometallic reagents with carbon dioxide. Angew. Chem., Int. Ed. 2009, 48, 6201– 6204, DOI: 10.1002/anie.200900667[Crossref], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpvFyhu7s%253D&md5=ca4ad574034905a13582de19db7e7c74Metal-Catalyzed Carboxylation of Organometallic Reagents with Carbon DioxideCorrea, Arkaitz; Martin, RubenAngewandte Chemie, International Edition (2009), 48 (34), 6201-6204CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Review on the recent advances in metal catalyzed carboxylation of organometallic reagents with carbon dioxide.
- 55Duffy, I. R.; Vasdev, N.; Dahl, K. Copper(I)-mediated 11C-carboxylation of (hetero)arylstannanes. ACS Omega. 2020, 5, 8242– 8250, DOI: 10.1021/acsomega.0c00524[ACS Full Text], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvF2gsb8%253D&md5=4603e151e132f20e060af207c3deaff9Copper(I)-Mediated 11C-Carboxylation of (Hetero)arylstannanesDuffy, Ian R.; Vasdev, Neil; Dahl, KennethACS Omega (2020), 5 (14), 8242-8250CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)A novel copper-mediated carboxylation strategy of aryl- and heteroaryl-stannanes was described. The method served as a mild (i.e., 1 atm) carboxylation method using stable carbon dioxide and was transferable as a radiosynthetic approach for carbon-11-labeled arom. and heteroarom. carboxylic acids using sub-stoichiometric quantities of [11C]CO2. The methodol. was applied to the radiosynthesis of the retinoid X receptor agonist, [11C]bexarotene, with a decay-cor. radiochem. yield of 32 ± 5% and molar activity of 38 ± 23 GBq/μmol (n = 3).
- 56Doi, H. Pd-mediated rapid cross-couplings using [(11)C]methyl iodide: Groundbreaking labeling methods in (11)C radiochemistry. J. Labelled Compd. Radiopharm. 2015, 58, 73– 85, DOI: 10.1002/jlcr.3253[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkvVaitb8%253D&md5=9055f285dc63e8ae5dccfd9607bdd5f9Pd-mediated rapid cross-couplings using [11C]methyl iodide: ground breaking labeling methods in 11C radiochemistryDoi, HisashiJournal of Labelled Compounds and Radiopharmaceuticals (2015), 58 (3), 73-85CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)A review. This paper presents a short summary of the background and the development of Pd-mediated rapid cross-couplings of [11C]methyl iodide, with a focus not only on organostannanes, but also on organoboranes, organozincs, and terminal acetylene compds. All these reactions have proven to be dependable 11C-labeling methodologies that use chem. reliable carbon-carbon bond formation reactions.
- 57Foresti, R.; Motterlini, R. Interaction of carbon monoxide with transition metals: Evolutionary insights into drug target discovery. Curr. Drug Targets 2010, 11, 1595– 1604, DOI: 10.2174/1389450111009011595[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKrtrbF&md5=7829af4aa2fd64d1405e1fe37985019cInteraction of carbon monoxide with transition metals: evolutionary insights into drug target discoveryForesti, Roberta; Motterlini, RobertoCurrent Drug Targets (2010), 11 (12), 1595-1604CODEN: CDTUAU; ISSN:1389-4501. (Bentham Science Publishers Ltd.)A review. The perception that carbon monoxide (CO) is poisonous and life-threatening for mammalian organisms stems from its intrinsic propensity to bind iron in Hb, a reaction that ultimately leads to impaired oxygen delivery to tissues. From evolutionary and chem. perspectives, however, CO is one of the most essential mols. in the formation of biol. components and its interaction with transition metals is at the origin of primordial cell signaling. Not surprisingly, mammals have gradually evolved systems to finely control the synthesis and the sensing of this gaseous mol. Cells are indeed continuously exposed to small quantities of CO produced endogenously during the degrdn. of heme by constitutive and inducible heme oxygenase enzymes. We have gradually learnt that heme oxygenase-derived carbon monoxide (CO) serves as a ubiquitous signaling mediator which could be exploited for therapeutic purposes. The development of transition metal carbonyls as prototypic carbon monoxide-releasing mols. (CO-RMs) represents a novel stratagem for a safer delivery of CO-based pharmaceuticals in the treatment of various pathol. disorders. This review looks back at evolution to analyze and argue that a dynamic interaction of CO with specific intracellular metal centers is the common denominator for the diversified beneficial effects mediated by this gaseous mol.
- 58Pretze, M.; Große-Gehling, P.; Mamat, C. Cross-coupling reactions as valuable tool for the preparation of PET radiotracers. Molecules 2011, 16, 1129– 1165, DOI: 10.3390/molecules16021129[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvFansrw%253D&md5=4f6701c98a520885e716fbd7836ce4eeCross-coupling reactions as valuable tool for the preparation of PET radiotracersPretze, Marc; Grosse-Gehling, Philipp; Mamat, ConstantinMolecules (2011), 16 (), 1129-1165CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. The increasing application of positron emission tomog. (PET) in nuclear medicine stimulated the extensive development of a multitude of new radiotracers and novel radiolabeling procedures with the most prominent short-lived positron emitters carbon-11 and fluorine-18. Radiolabeling with these radionuclides represents a remarkable challenge. Special attention paid to synthesis time and specific labeling techniques due to the short phys. half life of the resp. radionuclides 11C (t1/2 = 20.4 min) and 18F (t1/2 = 109.8 min). In the past, numerous transition metal-catalyzed reactions were employed in org. chem., even though only a handful of these coupling reactions were adopted in radiochem. practice. Thus, the implementation of modern synthesis methods like cross-coupling reactions offers the possibility to develop a wide variety of novel radiotracers. The introduction of catalysts based on transition metal complexes bears a high potential for rapid, efficient, highly selective and functional group-tolerating incorporation of carbon-11 and fluorine-18 into target mols. This review dealt with design, application and improvement of transition metal-mediated carbon-carbon as well as carbon-heteroatom cross-coupling reactions as a labeling feature with the focus on the prepn. of radiolabeled compds. for mol. imaging.
- 59Dahl, K.; Schou, M.; Amini, N.; Halldin, C. Palladium-mediated [11C]carbonylation at atmospheric pressure: A general method using xantphos as supporting ligand: Pd-mediated [11C]carbonylation at atmospheric pressure. Eur. J. Org. Chem. 2013, 2013, 1228– 1231, DOI: 10.1002/ejoc.201201708[Crossref], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1eqsLk%253D&md5=8753261cbe35114ce6ec315e823b42eePalladium-Mediated [11C]Carbonylation at Atmospheric Pressure: A General Method Using Xantphos as Supporting LigandDahl, Kenneth; Schou, Mangus; Amini, Nahid; Halldin, ChristerEuropean Journal of Organic Chemistry (2013), 2013 (7), 1228-1231CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)The palladium-catalyzed [11C]carbonylation of aryl halides and triflates was achieved at atm. pressure by employing xantphos as the supporting ligand. Aryl halides were converted into their corresponding [11C]amides in good to excellent yields. The conditions were also successfully employed in the radiolabeling of an [11C]ester, a [11C]carboxylic acid, an [11C]aldehyde, and a [11C]ketone.
- 60Xu, Y.; Kim, S. W.; Kim, D.; Alexoff, D.; Schueller, M. J.; Fowler, J. S. A mild, rapid synthesis of freebase [11C]nicotine from [11C]methyl triflate. Appl. Radiat. Isot. 2016, 118, 62– 66, DOI: 10.1016/j.apradiso.2016.08.020[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyit73J&md5=b7c1520f5d2c5fb4b5b27624b321f382A mild, rapid synthesis of freebase [11C]nicotine from [11C]methyl triflateXu, Youwen; Kim, Sung Won; Kim, Dohyun; Alexoff, David; Schueller, Michael J.; Fowler, Joanna S.Applied Radiation and Isotopes (2016), 118 (), 62-66CODEN: ARISEF; ISSN:0969-8043. (Elsevier Ltd.)A rapid, mild radiosynthesis of free base [11C]nicotine was developed by the methylation of free base nornicotine with [11C]methyl triflate in acetone (5 min, 45 °C). A basic (pH 10.5-11.0) HPLC system reproducibly yielded free base [11C]nicotine as a well-defined single peak. The free base [11C]nicotine was concd. by solid phase extn. and formulated in 50 μL ethanol (370 MBq/50 μL) without evaporative loss suitable for a cigarette spiking study. A radiochem. yield of 60.4±4.7% (n = 3), radiochem. purity ≥99.9% and specific activity of 648 GBq/μmol at EOB for 5 min beams were achieved.
- 61Saji, H.; Magata, Y.; Yamada, Y.; Tajima, K.; Yonekura, Y.; Konishi, J.; Ohmomo, Y.; Yokoyama, A. Synthesis of (S)-N-(methyl-11C)nicotine and its regional distribution in the mouse brain: A potential tracer for visualization of brain nicotinic receptors by positron emission tomography. Chem. Pharm. Bull. 1992, 40, 734– 736, DOI: 10.1248/cpb.40.734[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XisFWiurw%253D&md5=64e5aeaf8e65541a6685cc225d53a6f5Synthesis of (S)-N-[methyl[11C]nicotine and its regional distribution in the mouse brain: a potential tracer for visualization of brain nicotinic receptors by positron emission tomographySaji, Hideo; Magata, Yasuhiro; Yamada, Yoshihisa; Tajima, Ken; Yonekura, Yoshiharu; Konishi, Junji; Ohmomo, Yoshiro; Yokoyama, AkiraChemical & Pharmaceutical Bulletin (1992), 40 (3), 734-6CODEN: CPBTAL; ISSN:0009-2363.A nicotine agonist, 11C-labeled (S)-nicotine, was synthesized by N-methylation of (S)-nornicotine with 11CH3I Me iodide in DMS-DMSO to study nicotinic receptors in the human brain by positron emission tomog. The radiochem. yield of this N-methylation reaction was >90% within 5 min. After purifn. by HPLC the radiochem. purity of the product was >99% and the specific radioactivity was 7.4-11.1 GBq/μmol. The regional distribution of (S)-[11C]nicotine in the mouse brain after i.v. injection was compared with that of (R)-[11C]nicotine. After injection of (S)-[11C]nicotine, the regional uptake of radioactivity was in the following order: cortex > thalamus ≈ hippocampus > striatum > hypothalamus > cerebellum. Moreover, (S)-[11C]nicotine was displaced from the brain by unlabeled (S)-nicotine, but unlabeled (R)-nicotine caused no change in uptake. In contrast, (R)-[11C]nicotine showed a lower brain uptake and lesser regional differences in radioactivity.
- 62Ettrup, A.; Mikkelsen, J. D.; Lehel, S.; Madsen, J.; Nielsen, E. O.; Palner, M.; Timmermann, D. B.; Peters, D.; Knudsen, G. M. 11C-NS14492 as a novel PET Radioligand for imaging cerebral 7 nicotinic acetylcholine receptors: In vivo evaluation and drug occupancy measurements. J. Nucl. Med. 2011, 52, 1449– 1456, DOI: 10.2967/jnumed.111.088815[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1yisrrE&md5=31dc0d035440f28a9c6f9187c066832011C-NS14492 as a novel PET radioligand for imaging cerebral α7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurementsEttrup, Anders; Mikkelsen, Jens D.; Lehel, Szabolcs; Madsen, Jacob; Nielsen, Elsebet O.; Palner, Mikael; Timmermann, Daniel B.; Peters, Dan; Knudsen, Gitte M.Journal of Nuclear Medicine (2011), 52 (9), 1449-1456CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Small-mol. α7 nicotinic acetylcholine receptor (α7nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α7nAChR PET tracer would be important for in vivo quantification of α7nAChR binding in humans and to measure α7nAChR occupancy of α7nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of 11C-NS14492 as a selective α7nAChR PET radioligand. Methods: The high-affinity α7nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using 11C-Me triflate. Female Danish Landrace pigs were studied at baseline and after i.v. administration of blocking doses of either the α7nAChR partial agonist SSR180711 or the unlabeled NS14492. 11C-NS14492 was given as an i.v. bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compd. fraction was detd. with radio-high-performance liq. chromatog. PET data were quantified with a graphical anal. with arterial input; 11C-NS14492 regional distribution vols. were calcd., and α7nAChR occupancy was detd. using an occupancy plot. Results: 11C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α7nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution vols. of 11C-NS14492 in all examd. regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α7nAChR in vivo. Conclusion: We report here that 11C-NS14492 is the first, to our knowledge, PET radioligand for α7nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compd. is considered a promising PET tracer for in vivo measurements of α7nAChR binding in the human brain.
- 63Cai, L.; Xu, R.; Guo, X.; Pike, V. W. Rapid room-temperature 11C-methylation of arylamines with [11C]methyl iodide promoted by solid inorganic-bases in DMF. Eur. J. Org. Chem. 2012, 2012, 1303– 1310, DOI: 10.1002/ejoc.201101499[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xkt1CjtA%253D%253D&md5=ee3feec44d6a1a7f0201707d0800081eRapid Room-Temperature 11C-Methylation of Arylamines with [11C]Methyl Iodide Promoted by Solid Inorganic-Bases in DMFCai, Lisheng; Xu, Rong; Guo, Xuelei; Pike, Victor W.European Journal of Organic Chemistry (2012), 2012 (7), 1303-1310CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)[11C]Methyl iodide is the most widely used reagent for labeling radiotracers with carbon-11 (t1/2 = 20.4 min) for mol. imaging with positron emission tomog. However, some substrates for labeling, esp. primary arylamines and pyrroles, are sluggishly reactive towards [11C]methyl iodide. We found that insol. inorg. bases, esp. Li3N or Li2O, effectively promote rapid reactions (≤ 10 min) of such substrates with no-carrier-added [11C]methyl iodide in N,N-dimethylformamide (DMF) at room temp. to give 11C-methylated products, e.g. I, in useful radiochem. yields. In particular, we discovered that some primary arylamines in Li3N/DMF were converted into their corresponding formanilides, and that these were readily N-methylated with [11C]methyl iodide, which preceded easy basic hydrolysis to the desired [11C]N-Me secondary arylamines. The use of a solid base permitted selective reaction at an arylamino group and, in some cases, avoided undesirable side reactions, such as ester group hydrolysis. An ultrasound device proved useful to provide remote and const. agitation of the radioactive heterogeneous reaction mixts. but imparted no ultrasound-specific chem. effect.
- 64Slobbe, P.; Windhorst, A. D.; Adamzek, K.; Bolijn, M.; Schuit, R. C.; Heideman, D. A. M.; van Dongen, G. A. M. S.; Poot, A. J. Development of [11C]vemurafenib employing a carbon-11 carbonylative stille coupling and preliminary evaluation in mice bearing melanoma tumor xenografts. Oncotarget 2017, 8, 38337– 38350, DOI: 10.18632/oncotarget.16321[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cvoslKjtg%253D%253D&md5=21c2f985920c4b0536188d2f1c53fe81Development of [11C]vemurafenib employing a carbon-11 carbonylative Stille coupling and preliminary evaluation in mice bearing melanoma tumor xenograftsSlobbe Paul; Windhorst Albert D; Adamzek Kevin; Bolijn Marije; Schuit Robert C; van Dongen Guus A M S; Poot Alex J; Slobbe Paul; van Dongen Guus A M S; Heideman Danielle A MOncotarget (2017), 8 (24), 38337-38350 ISSN:.Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAFV600E mutation. The aim of this study was to develop vemurafenib as PET tracer to determine its potential for identification of tumors sensitive to vemurafenib treatment. Therefore, vemurafenib was labeled with carbon-11 and analyzed for its tumor targeting potential in melanoma xenografts Colo829 (BRAFV600E) and MeWo (BRAFwt) using autoradiography on tissue sections, in vitro tumor cell uptake studies and biodistribution studies in xenografted athymic nu/nu mice. [11C]vemurafenib was synthesized in 21 ± 4% yield (decay corrected, calculated from [11C]CO) in > 99% radiochemical purity and a specific activity of 55 ± 18 GBq/μmol. Similar binding of [11C]vemurafenib was shown during autoradiography and cellular uptake studies in both cell lines. Plasma metabolite analysis demonstrated > 95% intact [11C]vemurafenib in vivo at 45 minutes after injection, indicating excellent stability. Biodistribution studies confirmed the in vitro results, showing similar tumor-to-background ratios in both xenografts models. These preliminary results suggest that identification of BRAFV600E mutations in vivo using PET with [11C]vemurafenib will be challenging.
- 65Garcia, R.; Xavier, C.; Paulo, A.; Santos, I.; Kniess, T.; Bergmann, R.; Wüst, F. Synthesis and biological evaluation of S-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT 1A receptors by positron emission tomography (PET). J. Labelled Compd. Radiopharm. 2005, 48, 301– 315, DOI: 10.1002/jlcr.924[Crossref], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjslWrtb0%253D&md5=3b649a7ebe504dac27f0166aae75d44fSynthesis and biological evaluation of S-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT1A receptors by positron emission tomography (PET)Garcia, Raquel; Xavier, Catarina; Paulo, Antonio; Santos, Isabel; Kniess, Torsten; Bergmann, R.; Wuest, FrankJournal of Labelled Compounds & Radiopharmaceuticals (2005), 48 (4), 301-315CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)The novel 2-mercaptoimidazole derivs., 1-[4-((2-methoxyphenyl)-1-piperazinyl)-butyl]-2-mercaptoimidazole (3) and methyl[4-((2-methoxyphenyl)-1-piperazinyl))butyl] (2-mercapto-1-methylimidazol-5-yl)methanamide (8), were efficiently labeled with 11C through methylation of the thioketone function with [11C]methyl iodide. The resulting radioligands 1-[4-((2-methoxyphenyl)-1-piperazinyl))butyl]-2-thio[11C]-methylimidazole ([11C]9) and methyl[4-((2-methoxyphenyl)-1-piperazinyl))butyl] (2-thio[11C]methyl-1-methylimidazol-5-yl)-methanamide ([11C]10) were synthesized in radiochem. yields of 20-30% (decay-cor., related to [11C]CO2) at a specific radioactivity of 0.2-0.4 Ci/μmol within 40-45 min including HPLC-purifn. The radiochem. purity exceeded 99%. The ref. compds. 9 and 10 were tested in a competitive receptor binding assay to det. their affinity toward the 5-HT1A receptor. Both compds. exhibit excellent sub-nanomolar affinities (IC50 = 0.576 ± 0.008 nM (9); IC50 = 0.86 ± 0.02 nM (10)) for the 5-HT1A receptor while displaying a high selectivity towards the 5-HT2A subtype of receptors (IC50 > 480 nM). By contrast, compd. 9 also shows substantial binding for the alpha1-adrenergic receptor (IC50 = 3.00 ± 0.02 nM) when compared with compd. 10 (IC50 = 54.5 ± 0.6 nM). Preliminary biodistribution studies in rats showed an initial. Brain uptake of 1.14 ± 0.11 and 0.37 ± 0.04% ID/g after 5 min, which decreased to 0.18 ± 0.04 and 0.16 ± 0.01% ID/g after 60 min for compds. [11C]9 and [11C]10, resp. For both compds., the cerebellum and rest of the brain uptake are very similar at the different time points. Unlike [11C]9, the radioligand [11C]10 has significant uptake and retention in the adrenal glands. Due to their washout from the brain compds. [11C]9 and [11C]10 seem not to be good candidates as radioligands for imaging 5-HT1A receptors by PET.
- 66Roger, G.; Lagnel, B.; Besret, L.; Bramoullé, Y.; Coulon, C.; Ottaviani, M.; Kassiou, M.; Bottlaender, M.; Valette, H.; Dollé, F. Synthesis, radiosynthesis and in vivo evaluation of 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-[11C]one, as a potent NR1A/2B subtype selective NMDA PET radiotracer. Bioorg. Med. Chem. 2003, 11, 5401– 5408, DOI: 10.1016/j.bmc.2003.09.036[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpt1egu7k%253D&md5=9be98f98e659b6cd479eb14ef1407a5dSynthesis, radiosynthesis and In vivo evaluation of 5-[3-(4-Benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-[11C]one, as a potent NR1A/2B subtype selective NMDA PET radiotracerRoger, Gaelle; Lagnel, Beatrice; Besret, Laurent; Bramoulle, Yann; Coulon, Christine; Ottaviani, Michelle; Kassiou, Michael; Bottlaender, Michel; Valette, Heric; Dolle, FredericBioorganic & Medicinal Chemistry (2003), 11 (24), 5401-5408CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Recently, a new series of potent and highly subtype-selective 1-(heteroarylalkynyl)-4-benzylpiperidine antagonists of the NMDA receptors has been described by Pfizer Labs. In this series, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-one (I) was identified as a selective antagonist for the NR1A/2B subtype, displaying IC50 values for inhibition of the NMDA responses of 5.3 nM for this subtype (compared to NR1A/2A: 35 μM and NR1A/2C>100 μM) and was active in rat at a relatively low dosage (10 mg/kg po). Deriv. I has been synthesized in four chem. steps in good overall yield and labeled with carbon-11 T12: 20.4 min at its benzoimidazolone ring using [11C]phosgene. The pharmacol. profile of [11C]-I was evaluated in vivo in rats with biodistribution studies and brain radioactivity monitored with intracerebral radiosensitive β-microprobes. The brain uptake of [11C]-I was extremely low (0.07% I.D./mL on av. at 30 min) and rather uniform across the different brain structures. This in vivo brain regional distribution of [11C]-I did not match with autoradiog. or binding data obtained with other NR2B subtype-selective NMDA ligands. Competition studies with ifenprodil (20 mg/kg, i.p., 30 min before the radiotracer injection) failed to demonstrate specific binding of the radiotracer in the brain. In view of these results, and esp. considering the low brain penetration of the radiotracer, [11C]-I does not have the required properties for imaging NMDA receptors using positron emission tomog.
- 67Bramoullé, Y.; Puech, F.; Saba, W.; Valette, H.; Bottlaender, M.; George, P.; Dollé, F. Radiosynthesis of (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl] oxazolidin-2-[11C]one ([11C]SL25.1188), a novel radioligand for imaging monoamine oxidase-B with PET. J. Labelled Compd. Radiopharm. 2008, 51, 153– 158, DOI: 10.1002/jlcr.1492[Crossref], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlvVKgtrc%253D&md5=fbb2ba59a37fd1350c7b4efefac9c4f3Radiosynthesis of (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl]oxazolidin-2-[11C]one ([11C]SL25.1188), a novel radioligand for imaging monoamine oxidase-B with PETBramoulle, Yann; Puech, Frederic; Saba, Wadad; Valette, Heric; Bottlaender, Michel; George, Pascal; Dolle, FredericJournal of Labelled Compounds and Radiopharmaceuticals (2008), 51 (3), 153-158CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)Within a novel series of 2-oxazolidinones developed in the past by Sanofi-Synthelabo, I (SL25.1188), a compd. that inhibits selectively and competitively MAO-B in human and rat brain (Ki values of 2.9 and 8.5 nM for MAO-B, resp., and ED50 (rat): 0.6 mg/kg p.o.), was considered an appropriate candidate for imaging this enzyme with positron emission tomog. I was labeled with carbon-11 (T1/2: 20.38 min) in one chem. step using the following process: (i) reaction of [11C]phosgene with the corresponding ring-opened precursor (1.2-2.5 mg) at 100 °C for 2 min in dichloromethane (0.5 mL) followed by (ii) concn. to dryness of the reaction mixt. and finally (iii) semi-preparative HPLC purifn. on a Waters Symmetry C18. A total of 300-500 MBq of [11C]-I (>95% chem. and radiochem. pure) could be obtained within 30-32 min (Sep-pak-based formulation included) with specific radioactivities ranging from 50 to 70 GBq/μmol (3.5-7% decay-cor. radiochem. yield, based on starting [11C]CH4).
- 68Hicks, J. W.; Parkes, J.; Tong, J.; Houle, S.; Vasdev, N.; Wilson, A. A. Radiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors. Nucl. Med. Biol. 2014, 41, 688– 694, DOI: 10.1016/j.nucmedbio.2014.05.001[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFentb3M&md5=dcedea3b995995c96c88e7fa130378faRadiosynthesis and ex vivo evaluation of [11C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitorsHicks, Justin W.; Parkes, Jun; Tong, Junchao; Houle, Sylvain; Vasdev, Neil; Wilson, Alan A.Nuclear Medicine and Biology (2014), 41 (8), 688-694CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are the two primary enzymes that regulate the tone of endocannabinoid signaling. Although new PET radiotracers have been discovered for imaging FAAH in vivo, no such radiotracer exists for imaging MAGL. Here we report the radiosynthesis of five candidate MAGL radiotracers and their ex vivo evaluations in mice and rats.Candidate carbamate and urea MAGL inhibitors were radiolabeled at the carbonyl position by [11C]CO2 fixation. Radiotracers were administered (tail-vein injection) to rodents and brain uptake of radioactivity measured at early and late time points ex vivo. Specificity of uptake was explored by pretreatment with unlabeled inhibitors (2 mg/kg, i.p.) 30 min prior to radiotracer administration.All five candidate MAGL radiotracers were prepd. in high specific activity (> 65 GBq/μmol) and radiochem. purity (> 98%). Moderate brain uptake (0.2-0.8 SUV) was obsd. for each candidate while pretreatment did not reduce uptake for four of the five tested. For two candidates ([11C]12 and [11C]14), high retention of radioactivity was obsd. in the blood (ca. 10 and 4 SUV at 40 min) which was blocked by pretreatment with unlabeled inhibitors. The most promising candidate, [11C]18, demonstrated moderate brain uptake (ca. 0.8 SUV) which showed circa 50% blockade by pretreatment with unlabeled 18.One putative and four reported potent and selective MAGL inhibitors have been radiolabeled via [11C]CO2 fixation as radiotracers for this enzyme. Despite the promising in vitro pharmacol. profile, none of the five candidate radiotracers exhibited in vivo behavior suitable for PET neuroimaging.
- 69Wei, W.; Ni, D.; Ehlerding, E. B.; Luo, Q.-Y.; Cai, W. PET imaging of receptor tyrosine kinases in cancer. Mol. Cancer Ther. 2018, 17, 1625– 1636, DOI: 10.1158/1535-7163.MCT-18-0087[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVWrtrfL&md5=946d240d1ac024860ba3dc54f3b5e70ePET Imaging of Receptor Tyrosine Kinases in CancerWei, Weijun; Ni, Dalong; Ehlerding, Emily B.; Luo, Quan-Yong; Cai, WeiboMolecular Cancer Therapeutics (2018), 17 (8), 1625-1636CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Overexpression and/or mutations of the receptor tyrosine kinase (RTK) subfamilies, such as epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), are closely assocd. with tumor cell growth, differentiation, proliferation, apoptosis, and cellular invasiveness. Monoclonal antibodies (mAb) and tyrosine kinase inhibitors (TKI) specifically inhibiting these RTKs have shown remarkable success in improving patient survival in many cancer types. However, poor response and even drug resistance inevitably occur. In this setting, the ability to detect and visualize RTKs with noninvasive diagnostic tools will greatly refine clin. treatment strategies for cancer patients, facilitate precise response prediction, and improve drug development. Positron emission tomog. (PET) agents using targeted radioactively labeled antibodies have been developed to visualize tumor RTKs and are changing clin. decisions for certain cancer types. In the present review, we primarily focus on PET imaging of RTKs using radiolabeled antibodies with an emphasis on the clin. applications of these immunoPET probes. Mol Cancer Ther; 17(8); 1625-36. ©2018 AACR.
- 70Li, L.; Liu, S.; Liu, L.; Ma, Z.; Feng, M.; Ye, C.; Zhou, W.; Wang, Y.; Liu, L.; Wang, F.; Yu, L.; Zhou, F.; Xiang, Y.; Huang, S.; Fu, Q.; Zhang, Q.; Gao, D.; Yu, Z. Impact of phosphorylated insulin-like growth factor-1 receptor on the outcome of breast cancer patients and the prognostic value of its alteration during neoadjuvant chemotherapy. Exp. Ther. Med. 2018, 16, 2949– 2959, DOI: 10.3892/etm.2018.6584[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czgs1CntA%253D%253D&md5=ad47d34dfb9cfc816f64511150917647Impact of phosphorylated insulin-like growth factor-1 receptor on the outcome of breast cancer patients and the prognostic value of its alteration during neoadjuvant chemotherapyLi Liang; Liu Shuchen; Liu Liyuan; Ma Zhongbing; Ye Chunmiao; Zhou Wenzhong; Wang Yongjiu; Liu Lu; Wang Fei; Yu Lixiang; Zhou Fei; Xiang Yujuan; Huang Shuya; Fu Qinye; Zhang Qiang; Gao Dezong; Yu Zhigang; Liu Shuchen; Ye Chunmiao; Zhou Wenzhong; Liu Lu; Feng ManExperimental and therapeutic medicine (2018), 16 (4), 2949-2959 ISSN:1792-0981.The expression of insulin-like growth factor-1 receptor (IGF-1R), which is involved in the genesis and progression of breast cancer, is thought to be associated with the overall survival (OS) of patients. However, the predictive and prognostic significance of the IGF-1R expression in breast cancer remains controversial. The present study aimed to identify the factors associated with the levels of phosphorylated (p)-IGF-1R in breast cancer, their impact on the outcomes of breast cancer patients, and the prognostic value of alterations of p-IGF-1R during neoadjuvant chemotherapy (NAC). The present study included 348 female breast cancer patients whose paraffin-embedded tumor tissue sections had been collected by biopsy and/or resection, among which the pre-NAC and post-NAC sections were available from 40 patients. Human epidermal growth factor receptor 2 (HER2) positivity and molecular subtype were significantly associated with the presence of p-IGF-1R in the tumor tissue (P<0.05). Patients with p-IGF-1R present in the tumor tissue had a shorter OS (P=0.003). The p-IGF-1R levels in the tumor after NAC differed significantly from those prior to NAC (P=0.005); however, this alteration in p-IGF-1R levels was not associated with a shorter OS. In parallel with HER2, p-IGF-1R appears to be a promising indicator for predicting clinical outcomes and may be an attractive target for improving the efficacy of antitumor therapy, particularly for patients with HER2-negative, estrogen receptor-positive and luminal B tumors.
- 71Tegnebratt, T.; Lu, L.; Eksborg, S.; Chireh, A.; Damberg, P.; Nikkhou-Aski, S.; Foukakis, T.; Rundqvist, H.; Holmin, S.; Kuiper, R. V.; Samen, E. Treatment response assessment with (R)-[11CPAQ PET in the MMTV-PyMT mouse model of breast cancer. EJNMMI Res. 2018, 8, 25, DOI: 10.1186/s13550-018-0380-x[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MnovVWiuw%253D%253D&md5=4bb2095c3613104b3793516da1e85c37Treatment response assessment with (R)-[(11)CPAQ PET in the MMTV-PyMT mouse model of breast cancerTegnebratt T; Lu L; Chireh A; Damberg P; Nikkhou-Aski S; Holmin S; Samen E; Tegnebratt T; Holmin S; Samen E; Lu L; Damberg P; Nikkhou-Aski S; Eksborg S; Foukakis T; Rundqvist H; Kuiper R VEJNMMI research (2018), 8 (1), 25 ISSN:2191-219X.BACKGROUND: The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[(11)C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models. METHODS: MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[(11)C]PAQ PET as standardized uptake value (SUV)mean, SUVmax relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[(11)C]PAQ radiotracer uptake and therapy response biomarkers. RESULTS: The (R)-[(11)C]PAQ SUVmax in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUVmax change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[(11)C]PAQ SUVmax change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups. CONCLUSIONS: The results of this study are promising. However, additional studies are necessary before (R)-[(11)C]PAQ can be approved as a predictive radiotracer for cancer therapy response.
- 72van Dongen, G. A. M. S.; Visser, G. W. M.; Lub-De Hooge, M. N.; de Vries, E. G.; Perk, L. R. Immuno-PET: A navigator in monoclonal antibody development and applications. Oncologist 2007, 12, 1379– 1389, DOI: 10.1634/theoncologist.12-12-1379[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhslSntLs%253D&md5=66ffadf35003a3866e6ce263a33dedd2Immuno-PET: a navigator in monoclonal antibody development and applicationsvan Dongen, Guus A. M. S.; Visser, Gerard W. M.; Lub-de Hooge, Marjolijn N.; de Vries, Elisabeth G.; Perk, Lars R.Oncologist (2007), 12 (12), 1379-1389CODEN: OCOLF6; ISSN:1083-7159. (AlphaMed Press)A review. Monoclonal antibodies (mAbs) have been approved for use as diagnostics and therapeutics in a broad range of medical indications, but esp. in oncol. In addn., hundreds of new mAbs, engineered mAb fragments, and nontraditional antibody-like scaffolds directed against either validated or novel tumor targets are under development. Immuno-positron emission tomog. (PET), the tracking and quantification of mAbs with PET in vivo, is an exciting novel option to improve diagnostic imaging and to guide mAb-based therapy. In this review, recent tech. advances leading to a jump ahead in mAb imaging are discussed. The availability of proper positron emitters, sophisticated radiochem., and advanced PET and PET-computed tomog. scanners is crucial in these developments. Immuno-PET might play an important future role in cancer staging, in the improvement and tailoring of therapy with existing mAbs, and in the efficient development of novel mAbs. An overview of the preclin. and first clin. immuno-PET studies is provided.
- 73Weber, B.; Winterdahl, M.; Memon, A.; Sorensen, B. S.; Keiding, S.; Sorensen, L.; Nexo, E.; Meldgaard, P. Erlotinib accumulation in brain metastases from non-small cell lung cancer: Visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J. Thorac. Oncol. 2011, 6, 1287– 1289, DOI: 10.1097/JTO.0b013e318219ab87[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MjmvV2rsA%253D%253D&md5=a00d4acc3aec6b71157da49fdf4732f0Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptorWeber Britta; Winterdahl Michael; Memon Ashfaque; Sorensen Boe S; Keiding Susanne; Sorensen Leif; Nexo Ebba; Meldgaard PeterJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2011), 6 (7), 1287-9 ISSN:.INTRODUCTION: Drugs directed toward the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva®) and gefitinib (Iressa®), are used for the treatment of patients with advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. However, whether erlotinib actually enters into brain metastases has not been adequately elucidated. In this study, we investigated the accumulation of [11C]-erlotinib by positron emission tomography (PET) combined with computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: A 32-year-old patient with NSCLC and multiple brain metastases was treated with first-line erlotinib. EGFR mutations were determined by analyzing a fine-needle lung tumor biopsy taken before the treatment. A PET/CT of the brain with [11C]-erlotinib was performed during treatment, and a MRI of the head and a CT of the chest were performed pre- and posttreatment. RESULTS: The primary lung tumor displayed an erlotinib-sensitizing exon 19 deletion in the EGFR gene, and [11C]-erlotinib PET/CT showed accumulation in the brain metastases. Posttreatment MRI and CT demonstrated regression of both brain metastases and primary lung tumor. CONCLUSION: Our data demonstrated that erlotinib accumulated in brain metastases in a NSCLC patient who responded to the treatment.
- 74Saleem, A.; Searle, G. E.; Kenny, L. M.; Huiban, M.; Kozlowski, K.; Waldman, A. D.; Woodley, L.; Palmieri, C.; Lowdell, C.; Kaneko, T.; Murphy, P. S.; Lau, M. R.; Aboagye, E. O.; Coombes, R. C. Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer. EJNMMI Res. 2015, 5, 30, DOI: 10.1186/s13550-015-0103-5[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfktlOgtQ%253D%253D&md5=244029e3a9f8a69486ffba1fb4e56bfdLapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancerSaleem Azeem; Searle Graham E; Huiban Mickael; Kenny Laura M; Kozlowski Kasia; Aboagye Eric O; Coombes Raoul C; Waldman Adam D; Woodley Laura; Palmieri Carlo; Lowdell Charles; Kaneko Tomomi; Murphy Philip S; Lau Mike REJNMMI research (2015), 5 (), 30 ISSN:2191-219X.BACKGROUND: Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access. METHODS: Patients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([(11)C]lapatinib)-PET. Less than 20 μg of [(11)C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted. RESULTS: Six patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [(11)C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [(11)C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [(11)C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib. CONCLUSIONS: Increased lapatinib uptake was observed in brain metastases but not in normal brain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01290354.
- 75Varrone, A.; Varnäs, K.; Jucaite, A.; Cselényi, Z.; Johnström, P.; Schou, M.; Vazquez-Romero, A.; Moein, M. M.; Halldin, C.; Brown, A. P.; Vishwanathan, K.; Farde, L. A PET study in healthy subjects of brain exposure of 11C-labelled osimertinib - A drug intended for treatment of brain metastases in non-small cell lung cancer. J. Cereb. Blood Flow Metab. 2020, 40, 799– 807, DOI: 10.1177/0271678X19843776[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvF2qsbg%253D&md5=a466648d161c31693a18f1b314c2653bA PET study in healthy subjects of brain exposure of 11C-labelled osimertinib - A drug intended for treatment of brain metastases in non-small cell lung cancerVarrone, Andrea; Varnaes, Katarina; Jucaite, Aurelija; Cselenyi, Zsolt; Johnstroem, Peter; Schou, Magnus; Vazquez-Romero, Ana; Moein, Mohammad M.; Halldin, Christer; Brown, Andrew P.; Vishwanathan, Karthick; Farde, LarsJournal of Cerebral Blood Flow & Metabolism (2020), 40 (4), 799-807CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)Osimertinib is a tyrosine kinase inhibitor (TKI) of mutated epidermal growth factor receptor (EGFRm) with obsd. efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to det. brain distribution and exposure of 11C-labeled osimertinib administered i.v. in subjects with an intact blood-brain barrier. Eight male healthy subjects (age 52 ± 8 years) underwent one PET measurement with 11C-osimertinib. The pharmacokinetic parameters Cmax(brain) (standardized uptake value), Tmax(brain) and AUC0-90 minbrain/blood ratio were calcd. The outcome measure for 11C-osimertinib brain exposure was the total distribution vol. (VT). 11C-osimertinib distributed rapidly to the brain, with higher uptake in gray than in white matter. Mean Cmax, Tmax and AUC0-90 minbrain/blood ratio were 1.5 (range 1-1.8), 13 min (range 5-30 min), and 3.8 (range 3.3-4.1). Whole brain and white matter VT were 14 mLxcm-3 (range 11-18) and 7 mLxcm-3 (range 5-12). This study in healthy volunteers shows that 11C-osimertinib penetrates the intact blood-brain barrier. The approach used further illustrates the role of mol. imaging in facilitating the development of novel drugs for the treatment of malignancies affecting the brain.
- 76Zheng, Q.-H.; Stone, K. L.; Mock, B. H.; Miller, K. D.; Fei, X.; Liu, X.; Wang, J.-Q.; Glick-Wilson, B. E.; Sledge, G. W.; Hutchins, G. D. [11C]choline as a potential PET marker for imaging of breast cancer athymic mice. Nucl. Med. Biol. 2002, 29, 803– 807, DOI: 10.1016/S0969-8051(02)00339-6[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XovFKjt7g%253D&md5=dc6660a52cdaf28546afd5e20512d6bf[11C]choline as a potential PET marker for imaging of breast cancer athymic miceZheng, Qi-Huang; Stone, K. Lee; Mock, Bruce H.; Miller, Kathy D.; Fei, Xiangshu; Liu, Xuan; Wang, Ji-Quan; Glick-Wilson, Barbara E.; Sledge, George W.; Hutchins, Gary D.Nuclear Medicine and Biology (2002), 29 (8), 803-807CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)[11C]Choline has been evaluated as a potential positron emission tomog. (PET) marker for imaging of breast cancer. The biodistribution of [11C]choline was detd. at 45 min post iv injection in MCF-7's transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptake of [11C]choline in these tumors was high, 2.0% dose/g in MCF-7's transfected with IL-1alpha implanted mice and 1.8% dose/g in MDA-MB-435 implanted mice; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.7 (T/M, MCF-7's), 2.1 (T/M, MDA-MB-435) and 6.9 (T/B, MCF-7's), 12.5 (T/B, MDA-MB-435), resp.; the tumor/muscle ratios are moderate, and the tumor/blood ratios are high. The micro-PET imaging of [11C]choline in both breast cancer athymic mice was acquired for 15 min from a MCF-7's transfected with IL-1alpha and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resoln. (<3 mm full-width at half-max.) small FOV (field-of-view) PET imaging system, Indy-PET II scanner, developed in our lab., which showed the uptake of [11C]choline in MCF-7's transfected with IL-1alpha tumor or MDA-MB-435 tumor implanted in a nude athymic mouse. These results suggest that [11C]choline may be a potential PET breast cancer imaging agent.
- 77Hara, T.; Kosaka, N.; Kishi, H. PET imaging of prostate cancer using carbon-11-choline. J. Nucl. Med. 1998, 39, 990– 995[PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXktV2itrg%253D&md5=8556569bbe8650e1792490774700e1e2PET imaging of prostate cancer using carbon-11-cholineHara, Toshihiko; Kosaka, Noboru; Kishi, HiroichiJournal of Nuclear Medicine (1998), 39 (6), 990-995CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Prostate cancer is difficult to visualize using current techniques. Recently, 31P magnetic resonance spectroscopy has revealed that the tumor, in general, is characterized by an increased uptake of choline into the cell to meet increased synthesis of phosphatidyl-choline, an important cell membrane phospholipid. We succeeded in using 11C-choline to visualize prostate cancer and its local metastasis in PET. PET was performed on 10 prostate cancer patients from the level of pelvis to the lower abdomen. After transmission scanning, 370 MBq 11C-choline were injected i.v. The emission scan was performed 5-15 min postinjection. Finally, PET images were displayed so that each pixel was painted by a specified color representing the degree of the standardized uptake value (SUV). The 11C-choline image was compared with the 18F-fluorodeoxyglucose (FDG) image obtained from the same patient. Imaging of prostate cancer and its local metastasis was difficult when 18F-FDG was used because, within the pelvis, the areas of high uptake were concealed by the overwhelmingly abundant radioactivity in urine (in ureters and bladder). By contrast, it was easy when 11C-choline was used because the urinary activity was negligible and tumor uptake was marked. The radioactivity concn. of 11C-choline in prostate cancer and metastatic sites was at an SUV of more than three in most cases. The SUV of 18F-FDG was considerably lower than that of 11C-choline. Prostate cancer and its local metastasis were visualized clearly in PET using 11C-choline.
- 78Hara, T.; Kosaka, N.; Shinoura, N.; Kondo, T. PET imaging of brain tumor with [methyl-11C]choline. J. Nucl. Med. 1997, 38, 842– 847[PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXksVWkurw%253D&md5=b027efcf9405dfeb049b5704f5bcc4bePET imaging of brain tumor with [methyl-11C]cholineHara, Toshihiko; Kosaka, Noboru; Shinoura, Nobusada; Kondo, TatsuyaJournal of Nuclear Medicine (1997), 38 (6), 842-847CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)This article describes a new method of [11C]choline synthesis for i.v. injection. We aimed at the utilization of this compd. for brain tumor imaging with PET. After [11C]carbon dioxide prodn. in a cyclotron and the subsequent [11C]methyl iodide synthesis, [methyl-11C]choline was synthesized by the reaction of [11C]methyl iodide with "neat" dimethylaminoethanol at 120°C for 5 min. Purifn. was achieved by evapn. of the reactants followed by passage of the aq. soln. of the product through a cation-exchange resin cartridge. The time required for overall chem. processing, excluding the cyclotron operation, was 15 min. Radiochem. yield was >98%. Radiochem. purity was >98%. Chem. purity was >90% (dimethylaminoethanol was the only possible impurity). Specific radioactivity of the product was >133 GBq/μmol. The whole body distribution was examd. in rabbits with PET. Clin. studies were performed in patients with brain tumor using PET after i.v. injection of 370 MBq of [11C]choline. In rabbits, [11C]choline was taken up from blood by various tissues very rapidly, and the radioactivity remaining in blood became almost negligible 5 min after i.v. injection. Taking advantage of this characteristic, we obtained stable tissue distribution images of human brain using PET. In patients with brain tumor, PET produced clearly delineated pos. images of the tumors. Carbon-11-choline can be used for obtaining clear images of brain tumor in PET.
- 79DeGrado, T. R.; Baldwin, S. W.; Wang, S.; Orr, M. D.; Liao, R. P.; Friedman, H. S.; Reiman, R.; Price, D. T.; Coleman, R. E. Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers. J. Nucl. Med. 2001, 42, 1805– 1814[PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XktlOktb8%253D&md5=5a95d32aa66f9089758b6890e3ca6bbcSynthesis and evaluation of 18F-labeled choline analogs as oncologic PET tracersDeGrado, Timothy R.; Baldwin, Steven W.; Wang, Shuyan; Orr, Matthew D.; Liao, Ray P.; Friedman, Henry S.; Reiman, Robert; Price, David T.; Coleman, R. EdwardJournal of Nuclear Medicine (2001), 42 (12), 1805-1814CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Elevated levels of choline (trimethyl-2-hydroxyethylammonium) and choline kinase (CK) activity in neoplasms have motivated the development of positron-labeled choline analogs for noninvasive detection of cancer using PET. The aim of this study was to further evaluate [18F]fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) as an oncol. probe in comparison with several other closely related mols. FCH, [18F]fluoromethyl-methylethyl-2-hydroxyethylammonium (FMEC), [18F]fluoroethyl-dimethyl-2-hydroxyethylammonium (FEC), and [18F]fluoropropyl-dimethyl-2-hydroxyethylammonium (FPC) were synthesized through [18F]fluoroalkylation reactions. In vitro phosphorylation rates of the 18F-labeled choline analogs and [methyl14C]choline (CH) were studied using yeast CK. Several choline radiotracers were also evaluated in cultured PC-3 human prostate cancer cells. Data on chem. stability, radiation dosimetry, and toxicity of FCH were obtained. PET studies with FCH were performed on a patient with prostate cancer and a patient with a brain tumor. FCH and FMEC revealed in vitro phosphorylation by CK that was similar to that of choline, whereas rates of phosphorylation of FEC and FPC were 30% (P < 0.01) and 60% (P < 0.01) lower, resp. Accumulations of FCH, CH, and FPC in cultured PC-3 cancer cells were comparable, whereas uptake of FEC was approx. one fifth that of FCH. Dosimetry ests. using FCH biodistribution data in mice indicated that the kidneys are radiation-dose-crit. organs for FCH. PET images of a patient with recurrent prostate cancer showed uptake of FCH in the prostatic bed and in metastases to lymph nodes. FCH PET showed uptake in malignancies in a patient with metastatic breast cancer. PET revealed FCH uptake in biopsy-proven recurrent brain tumor with little confounding uptake by normal brain tissues. The fluoromethyl choline analog FCH may serve as a probe of choline uptake and phosphorylation in cancer cells, whereas fluoroethyl (FEC) and fluoropropyl (FPC) analogs appear to have relatively poorer biol. compatibility. Preliminary PET studies on patients with prostate cancer and with breast cancer and brain tumor support further studies to evaluate the usefulness of FCH as an oncol. probe.
- 80Ohtani, T.; Kurihara, H.; Ishiuchi, S.; Saito, N.; Oriuchi, N.; Inoue, T.; Sasaki, T. Brain tumour imaging with carbon-11 choline: Comparison with FDG PET and gadolinium-enhanced MR imaging. Eur. J. Nucl. Med. 2001, 28, 1664– 1670, DOI: 10.1007/s002590100620[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvFGhsbY%253D&md5=209800ec166ef31348a286a8f16068a6Brain tumour imaging with carbon-11 choline: comparison with FDG PET and gadolinium-enhanced MR imagingOhtani, Toshiyuki; Kurihara, Hideyuki; Ishiuchi, Shogo; Saito, Nobuhito; Oriuchi, Noboru; Inoue, Tomio; Sasaki, TomioEuropean Journal of Nuclear Medicine (2001), 28 (11), 1664-1670CODEN: EJNMD9; ISSN:0340-6997. (Springer-Verlag)The purpose of this study was to assess the clin. potential of methyl-11C-choline (11C-choline) in the diagnosis of brain tumors. To this end, the results of 11C-choline positron emission tomog. (PET) in 22 patients suspected of having brain tumors were compared with the findings of contrast-enhanced magnetic resonance (MR) imaging and fluorine-18 fluorodeoxyglucose PET. A histopathol. diagnosis was made for each patient during open surgery. The standardized uptake values of brain tumors and the tumor-to-white matter count (T/W) ratios were detd. The degree of 11C-choline accumulation noted in PET images was compared with the gadolinium-enhanced areas of MR images. The mean T/W ratio of 11C-choline in high-grade gliomas was found to be higher than that in low-grade gliomas. This difference was statistically significant (mean±SD: 8.7±6.2, n=9 vs. 1.5±0.7, n=5, P<0.03) when data pertaining to the prominent uptake of 11C-choline in a patient with a pilocytic astrocytoma were excluded. 11C-choline PET failed to detect non-neoplastic lesions in two patients. Areas of 11C-choline accumulation in PET scans were larger than areas enhanced on MR images in five cases involving high-grade gliomas. 11C-choline PET differentiated between low-grade gliomas and high-grade gliomas, but did not differentiate between low-grade gliomas and non-neoplastic lesions. The combination of 11C-choline PET and MR imaging may provide investigators with an accurate means by which to identify high-grade gliomas.
- 81Giovacchini, G.; Fallanca, F.; Landoni, C.; Gianolli, L.; Picozzi, P.; Attuati, L.; Terreni, M.; Picchio, M.; Messa, C.; Fazio, F. C-11 choline versus F-18 fluorodeoxyglucose for imaging meningiomas: An initial experience. Clinical Nuclear Medicine. 2009, 34, 7– 10, DOI: 10.1097/RLU.0b013e31818f4369[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M%252FjvVKrtw%253D%253D&md5=42451271f4e399e339f6f7308963beb7C-11 choline versus F-18 fluorodeoxyglucose for imaging meningiomas: an initial experienceGiovacchini Giampiero; Fallanca Federico; Landoni Claudio; Gianolli Luigi; Picozzi Piero; Attuati Luca; Terreni Mariarosa; Picchio Maria; Messa Cristina; Fazio FerruccioClinical nuclear medicine (2009), 34 (1), 7-10 ISSN:.PURPOSE: Positron emission tomography/computed tomography (PET/CT) with C-11 choline has been used for staging, restaging, and follow-up of various tumors, whereas its role for imaging meningiomas has only been preliminarily explored. The aim of this study was to compare C-11 choline and F-18 fluorodeoxyglucose (F-18 FDG) uptake in meningiomas and relate these findings to the histopathological analysis. METHODS: Two sequential three-dimensional PET/CT scans with 370 MBq (10 mCi) of C-11 choline and 370 MBq (10 mCi) of F-18 FDG were performed 2 hours apart in 7 patients with histologically confirmed meningiomas. Five patients had WHO grade I and 2 had WHO grade II meningioma. For each scan, two-dimensional regions of interest were drawn on tumor boundaries and on the contralateral side on CT images and copied to the corresponding PET images. SUVmax and tumor-to-background ratio were calculated. RESULTS: Relative to the contralateral side, C-11 choline uptake was increased in all meningiomas, whereas F-18 FDG uptake was decreased in 6 patients and increased in 1 of the 2 patients with grade II meningiomas. In the whole group, SUVmax of C-11 choline and F-18 FDG were 3.6 +/- 1.3 and 5.7 +/- 1.3, respectively. The tumor-to-background ratio for C-11 choline was much higher than that for F-18 FDG (5.3 +/- 0.8 vs. 0.9 +/- 0.2, respectively) (P < 0.001). The uptake of C-11 choline was higher in patients with grade II than in grade I meningiomas. CONCLUSIONS: These preliminary results suggest that C-11 choline may better image meningiomas in comparison with F-18 FDG. Clinical applications of C-11 choline PET/CT for grading and follow-up of meningiomas need to be assessed in further studies.
- 82Giovannini, E.; Lazzeri, P.; Milano, A.; Gaeta, M.; Ciarmiello, A. Clinical applications of choline PET/CT in brain tumors. Curr. Pharm. Des. 2014, 21, 121– 127, DOI: 10.2174/1381612820666140915120742
- 83Giovacchini, G.; Picchio, M.; Garcia-Parra, R.; Mapelli, P.; Briganti, A.; Montorsi, F.; Gianolli, L.; Messa, C. [11C]choline positron emission tomography/computerized tomography for early detection of prostate cancer recurrence in patients with low increasing prostate specific antigen. J. Urol. 2013, 189, 105– 110, DOI: 10.1016/j.juro.2012.09.001[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s7ks1Wqsw%253D%253D&md5=0ba9d876db863f0955e1114e522b694711C]choline positron emission tomography/computerized tomography for early detection of prostate cancer recurrence in patients with low increasing prostate specific antigenGiovacchini Giampiero; Picchio Maria; Garcia-Parra Rita; Mapelli Paola; Briganti Alberto; Montorsi Francesco; Gianolli Luigi; Messa CristinaThe Journal of urology (2013), 189 (1), 105-10 ISSN:.PURPOSE: The effectiveness of salvage therapy in prostate cancer is greater for low prostate specific antigen values. Therefore, early detection of tumor recurrence is warranted. [(11)C]choline positron emission tomography/computerized tomography has the potential of early restaging of prostate cancer with low prostate specific antigen, but the selection of patients at high risk for positive [(11)C]choline positron emission tomography/computerized tomography is desirable to optimize salvage therapy. MATERIALS AND METHODS: This retrospective study included 75 patients with prostate cancer with an increasing prostate specific antigen less than 1.5 ng/ml after radical prostatectomy who never received antiandrogen deprivation therapy or salvage radiotherapy who underwent [(11)C]choline positron emission tomography/computerized tomography for the restaging of disease. Binary logistic regression was used to assess predictive factors of positive [(11)C]choline positron emission tomography/computerized tomography. Included variables were trigger prostate specific antigen, prostate specific antigen doubling time, age, pathological stage and Gleason score. RESULTS: Median prostate specific antigen was 0.61 ng/ml. [(11)C]choline positron emission tomography/computerized tomography was positive in 16 of 75 patients (21%). On univariate analysis prostate specific antigen doubling time less than 6 months was the only factor significantly associated with an increased risk of positive [(11)C]choline positron emission tomography/computerized tomography (OR 7.77, 95% CI 2.34-25.80, p = 0.001). In patients with prostate specific antigen doubling time less than 6 months, the positive detection rate of [(11)C]choline positron emission tomography/computerized tomography increased to 50%. CONCLUSIONS: In patients with prostate cancer with biochemical failure after radical prostatectomy and prostate specific antigen less than 1.5 ng/ml, prostate specific antigen doubling time less than 6 months predicts positive [(11)C]choline positron emission tomography/computerized tomography. In these patients [(11)C]choline positron emission tomography/computerized tomography may reduce by 50% the number in whom salvage therapy is initiated empirically without knowing the disease location.
- 84Lindenberg, L.; Choyke, P.; Dahut, W. Prostate cancer imaging with novel PET tracers. Curr. Urol Rep. 2016, 17, 18, DOI: 10.1007/s11934-016-0575-5[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jgslCksw%253D%253D&md5=2b6279d2c81159bf7f531436262f6016Prostate Cancer Imaging with Novel PET TracersLindenberg Liza; Choyke Peter; Dahut William; Lindenberg Liza; Choyke Peter; Dahut WilliamCurrent urology reports (2016), 17 (3), 18 ISSN:.Molecular imaging of prostate cancer is in a dynamic phase of development. Currently approved techniques are limited and researchers have been working on novel agents to improve accuracy in targeting and detecting prostate tumors. In addition, the complexity of various prostate cancer states also contributes to the challenges in evaluating suitable radiotracer candidates. We have highlighted nuclear medicine tracers that focus on mechanisms involved in bone metastasis, prostate cancer cell membrane synthesis, amino acid analogs, androgen analogs, and the prostate specific membrane antigen. Encouraging results with many of these innovative radiotracer compounds will not only advance diagnostic capabilities for prostate cancer but open opportunities for theranostic applications to treat this worldwide malignancy.
- 85Umbehr, M. H.; Muntener, M.; Hany, T.; Sulser, T.; Bachmann, L. M. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: A systematic review and meta-analysis. Eur. Urol. 2013, 64, 106– 117, DOI: 10.1016/j.eururo.2013.04.019[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3srptlWrug%253D%253D&md5=755f7d52261d4f2b62fd52651f7d4fe9The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysisUmbehr Martin H; Muntener Michael; Hany Thomas; Sulser Tullio; Bachmann Lucas MEuropean urology (2013), 64 (1), 106-17 ISSN:.CONTEXT: The role of positron emission tomography (PET) and PET/computed tomography (PET/CT) in prostate cancer (PCa) imaging is still debated, although guidelines for their use have emerged over the last few years. OBJECTIVE: To systematically review and conduct a meta-analysis of the available evidence of PET and PET/CT using 11C-choline and 18F-fluorocholine as tracers in imaging PCa patients in staging and restaging settings. EVIDENCE ACQUISITION: PubMed, Embase, and Web of Science (by citation of reference) were searched. Reference lists of review articles and included articles were checked to complement electronic searches. EVIDENCE SYNTHESIS: In staging patients with proven but untreated PCa, the results of the meta-analysis on a per-patient basis (10 studies, n = 637) showed pooled sensitivity, specificity, and diagnostic odds ratio (DOR) of 84% (95% confidence interval [CI], 68-93%), 79% (95% CI, 53-93%), and 20.4 (95% CI, 9.9-42.0), respectively. The positive and negative likelihood ratios were 4.02 (95% CI, 1.73-9.31) and 0.20 (95% CI, 0.11-0.37), respectively. On a per-lesion basis (11 studies, n = 5117), these values were 66% (95% CI, 56-75%), 92% (95% CI, 78-97%), and 22.7 (95% CI, 8.9-58.0), respectively, for pooled sensitivity, specificity, and DOR; and 8.29 (95% CI, 3.05-22.54) and 0.36 (95% CI, 0.29-0.46), respectively, for positive and negative likelihood ratios. In restaging patients with biochemical failure after local treatment with curative intent, the meta-analysis results on a per-patient basis (12 studies, n = 1055) showed pooled sensitivity, specificity, and DOR of 85% (95% CI, 79-89%), 88% (95% CI, 73-95%), and 41.4 (95% CI, 19.7-86.8), respectively; the positive and negative likelihood ratios were 7.06 (95% CI, 3.06-16.27) and 0.17 (95% CI, 0.13-0.22), respectively. CONCLUSIONS: PET and PET/CT imaging with 11C-choline and 18F-fluorocholine in restaging of patients with biochemical failure after local treatment for PCa might help guide further treatment decisions. In staging of patients with proven but untreated, high-risk PCa, there is limited but promising evidence warranting further studies. However, the current evidence shows crucial limitations in terms of its applicability in common clinical scenarios.
- 86Evangelista, L.; Zattoni, F.; Guttilla, A.; Saladini, G.; Zattoni, F.; Colletti, P. M.; Rubello, D. Choline PET or PET/CT and biochemical relapse of prostate cancer: A systematic review and meta-analysis. Clin Nucl. Med. 2013, 38, 305– 314, DOI: 10.1097/RLU.0b013e3182867f3c[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svlsVyqtQ%253D%253D&md5=f1af8c4db81e097a37afd0e5e53c8624Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysisEvangelista Laura; Zattoni Fabio; Guttilla Andrea; Saladini Giorgio; Zattoni Filiberto; Colletti Patrick M; Rubello DomenicoClinical nuclear medicine (2013), 38 (5), 305-14 ISSN:.AIM: The increase of prostate-specific antigen (PSA) after radical retropubic prostatectomy (RP) or external beam radiotherapy (EBRT) is the most sensitive tool for detecting prostate cancer (PCa) recurrence, although this measure cannot distinguish between local, regional, or distant recurrence. The aim of this meta-analysis was to evaluate the diagnostic performance of 18F-choline and 11C-choline PET or PET/CT in detection of locoregional or distant metastases in PCa. MATERIALS AND METHODS: Medline, Web of Knowledge, and Google Scholar search was carried out in order to select English-language articles dealing with diagnostic performance of both 18F-choline and 11C-choline PET for the detection of PCa recurrence after RP or EBRT. Articles were included only if absolute numbers of true-positive, true-negative, false-positive, and false-negative test results were available or derivable from the text and regarded local, lymph node, and distant metastases. Reviews, clinical reports, and editorial articles were excluded. All complete studies were re-analyzed thus performing a quantitative analysis. RESULTS: From the years 2000 to 2012, we found 53 complete articles that critically evaluated the role of choline PET in restaging patients with PCa recurrence. The meta-analysis was carried out and dealt with 19 selected studies (12 studies for all sites of disease, 3 for lymph node metastases, and 4 for local recurrence), with a total of 1555 patients. The meta-analysis provided a pooled sensitivity of 85.6% (95% CI: 82.9%-88.1%) and pooled specificity of 92.6% (95% CI: 90.1%-94.6%) for all sites of disease (prostatic fossa, lymph nodes, and bone), a pooled sensitivity of 75.4% (95% CI: 66.9%-82.6%) and pooled specificity of 82% (95% CI: 68.6%-91.4%) for prostatic fossa recurrence, and a pooled sensitivity of 100% (95% CI: 90.5%-100%) and pooled specificity of 81.8% (95% CI: 48.2%-97.7%) for lymph node metastases. The heterogeneity ranged between 0.00% and 88.6%. The diagnostic odds ratios were 62.123 (95% CI: 24.783-155.72), 5.869 (95% CI: 1.818-18.946), and 138.57 (95% CI: 11.27-1703.8), respectively, for all sites of disease, local recurrence, and lymph node disease. CONCLUSIONS: Choline PET and PET/CT represent high sensitivity and specificity techniques for the detection of locoregional and distant metastases in PCa patients with recurrence of disease. Moreover, a high diagnostic odds ratio was found for the identification of lymph node disease in patients with biochemical recurrence of PCa.
- 87Oyama, N.; Miller, T. R.; Dehdashti, F.; Siegel, B. A.; Fischer, K. C.; Michalski, J. M.; Kibel, A. S.; Andriole, G. L.; Picus, J.; Welch, M. J. 11C-acetate PET imaging of prostate cancer: Detection of recurrent disease at PSA relapse. J. Nucl. Med. 2003, 44, 549– 555[PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjtlKnsLY%253D&md5=74885bbe34c8f6839d0c38da14e989ec11C-Acetate PET imaging of prostate cancer: detection of recurrent disease at PSA relapseOyama, Nobuyuki; Miller, Tom R.; Dehdashti, Farrokh; Siegel, Barry A.; Fischer, Keith C.; Michalski, Jeff M.; Kibel, Adam S.; Andriole, Gerald L.; Picus, Joel; Welch, Michael J.Journal of Nuclear Medicine (2003), 44 (4), 549-555CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Patients with rising prostate-specific antigen (PSA) levels after definitive local therapy of prostate carcinoma present a diagnostic dilemma. A local recurrence would be amenable to addnl. local therapy with curative intent, whereas metastatic disease would require palliative androgen ablation therapy. In this study, we evaluated the effectiveness of PET with 11C-acetate (AC PET) for evaluation of patients with rising PSA after radical prostatectomy or radiation therapy. We also compared the reliability of AC PET in detecting recurrent prostate cancer with that of PET with 18F-FDG. Methods: Two groups of patients with PSA recurrence were enrolled in this study: group A, 30 patients after prostatectomy, and group B, 16 patients after radiation therapy. After administration of 1,110 MBq (30 mCi) of 11C-acetate, whole-body PET images were obtained. After allowing for 11C decay, 555 MBq (15 mCi) of 18F-FDG were administered and repeated whole-body imaging was performed. The PET findings were scored as pos. or neg. in each of the following regions: prostatic bed, pelvic nodes, paraaortic nodes, and other sites (bone or soft tissue). PET findings were correlated with those of CT, bone scintigraphy, and biopsy. Results: Twenty-seven of 46 AC PET studies (59%) had pos. findings, whereas only 8 18F-FDG PET studies had pos. findings (17%). Limiting the anal. to patients with findings confirmed by CT, bone scintigraphy, or biopsy or considered highly likely to represent tumor, 14 (30%) had disease identified by AC PET, whereas only 4 (9%) had disease identified by 18F-FDG PET. CT was performed on 22 patients and had pos. findings in 3 (14%). Thirteen of 22 patients (59%) with serum PSA > 3 ng/mL had pos. AC PET findings, whereas only 1 of 24 patients (4%) with serum PSA levels ≤ 3 ng/mL had pos. findings. Conclusion: AC PET demonstrates marked uptake in prostate cancer and has higher sensitivity than 18F-FDG PET. These preliminary data show that 11C-acetate is a promising tracer for detection of recurrent prostate cancer.
- 88Howard, B. V.; Howard, W. J. Lipids in normal and tumor cells in culture. Prog. Biochem. Pharmacol. 1975, 10, 135– 166[PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXksFKgsrY%253D&md5=6ef0957efd422856edc83a668acfac12Lipids in normal and tumor cells in cultureHoward, Barbara V.; Howard, William J.Progress in Biochemical Pharmacology (1975), 10 (Lipids Tumors), 135-66CODEN: PBPHAW; ISSN:0079-6085.A review with 153 refs., on the compn. and metab. of lipid classes (fatty acids, glycolipids, lipid esters, and phospholipids) in cells and membranes of cultured normal and neoplastic cells.
- 89Swinnen, J. V.; Van Veldhoven, P. P.; Timmermans, L.; De Schrijver, E.; Brusselmans, K.; Vanderhoydonc, F.; Van de Sande, T.; Heemers, H.; Heyns, W.; Verhoeven, G. Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem. Biophys. Res. Commun. 2003, 302, 898– 903, DOI: 10.1016/S0006-291X(03)00265-1[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhvFGqsLY%253D&md5=c0b853d5ab87ad8a10ec99d6b3e9d01fFatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomainsSwinnen, Johannes V.; Van Veldhoven, Paul P.; Timmermans, Leen; De Schrijver, Ellen; Brusselmans, Koen; Vanderhoydonc, Frank; Van de Sande, Tine; Heemers, Hannelore; Heyns, Walter; Verhoeven, GuidoBiochemical and Biophysical Research Communications (2003), 302 (4), 898-903CODEN: BBRCA9; ISSN:0006-291X. (Elsevier Science)Fatty acid synthase (FAS) is a key metabolic enzyme catalyzing the synthesis of long-chain satd. fatty acids. It plays a central role in the prodn. of surfactant in fetal lungs, in the supply of fatty components of milk, and in the conversion and storage of energy in liver and adipose tissue. Remarkably high levels of FAS expression are found in the majority of human epithelial cancers. As the role of FAS in cancer cells remains largely unknown, we have initiated studies to assess the fate of newly synthesized lipids in cancer cells and have estd. the contribution of FAS to the synthesis of specific lipid classes by treating the cells with small interfering RNAs targeting FAS. Here, we show that in cancer cells FAS plays a major role in the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. These are raft-aggregates implicated in key cellular processes including signal transduction, intracellular trafficking, cell polarization, and cell migration. These findings reveal a novel role for FAS, provide important new insights into the otherwise poorly understood mechanisms underlying the control of lipid compn. of membrane microdomains, and point to a link between FAS overexpression and dysregulation of membrane compn. and functioning in tumor cells.
- 90Buxton, D. B.; Nienaber, C. A.; Luxen, A.; Ratib, O.; Hansen, H.; Phelps, M. E.; Schelbert, H. R. Noninvasive quantitation of regional myocardial oxygen consumption in vivo with [1–11C]acetate and dynamic positron emission tomography. Circulation 1989, 79, 134– 142, DOI: 10.1161/01.CIR.79.1.134[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M%252FptVSrtQ%253D%253D&md5=67680ed1064f6603e8b45071638988f4Noninvasive quantitation of regional myocardial oxygen consumption in vivo with [1-11C]acetate and dynamic positron emission tomographyBuxton D B; Nienaber C A; Luxen A; Ratib O; Hansen H; Phelps M E; Schelbert H RCirculation (1989), 79 (1), 134-42 ISSN:0009-7322.The usefulness of [1-11C]acetate as a tracer of overall myocardial oxidative metabolism for use with positron emission tomography has been investigated in 12 closed-chest dogs. Myocardial 11C activity clearance kinetics after intravenous administration of [1-11C]acetate in dogs have been determined noninvasively by positron emission tomography. Biexponential fitting of regional myocardial 11C time-activity curves was performed to give clearance half-times and fractional distribution. The rate constant k1 for the early rapid phase of 11C activity clearance was found to correlate linearly with myocardial oxygen consumption (y = 0.0156x + 0.039; SEE = 0.023; r = 0.95). k1 was approximately 7% lower in septal sectors compared with the left ventricular free wall, suggesting that regional oxygen consumption in the septum was lower; a concomitant regional attenuation of blood flow in the septum relative to the left ventricular free wall was also observed. In dogs using carbohydrates as the predominant fuel, k1 oxygen consumption was somewhat more than in dogs using predominantly free fatty acids (0.021 +/- 0.002 compared with 0.018 +/- 0.002, p less than 0.01), indicating that increased carbohydrate consumption is associated with a small increase in k1 at constant oxygen consumption. It is concluded that measurement of myocardial [1-11C]acetate kinetics allows noninvasive determination of cardiac oxygen consumption by positron emission tomography and that the technique is relatively insensitive to myocardial fuel selection.
- 91Cerdan, S.; Künnecke, B.; Seelig, J. Cerebral metabolism of [1,2–13C2]acetate as detected by in vivo and in vitro 13C NMR. J. Biol. Chem. 1990, 265, 12916– 12926, DOI: 10.1016/S0021-9258(19)38247-X[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXkvFGhsbk%253D&md5=e59b2944465b9370d5d0d62099661e34Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro carbon-13 NMRCerdan, Sebastian; Kuennecke, Basil; Seelig, JoachimJournal of Biological Chemistry (1990), 265 (22), 12916-26CODEN: JBCHA3; ISSN:0021-9258.The metab. of [1,2-13C2]acetate in rat brain was studied by in vivo and in vitro 13C NMR spectroscopy, in particularly by taking advantage of the homonuclear 13C-13C spin coupling patterns. Well-nourished rats were infused with [1,2-13C2]acetate or [1-13C]acetate in the jugular vein, and the in situ kinetics of 13C labeling during the infusion period were followed by 13C NMR techniques. The in vivo 13C NMR spectra showed signals from (1) the C-1 carbon of [1,2-13C2]acetate or [1-13C]acetate, (2) 13CO3H-, and (3) the natural abundance 13C carbons of sufficiently mobile fatty acids. Methanol/HCl/perchloric acid exts. of the brains were prepd. and were further analyzed by high-resoln. 13C NMR. The homonuclear 13C-13C spin coupling patterns after infusion of [1,2-13C2]acetate showed very different isotopomer populations in glutamate, glutamine, and GABA. Analyzing the relative proportions of these isotopomers revealed (1) 2 different glutamate compartments in the rat brain characterized by the presence and absence, resp., of glutamine synthase activity, (2) 2 different tricarboxylic acid cycles, 1 preferentially metabolizing [(1,2-13C2]acetate, the other mainly using unlabeled acetyl-CoA, (3) a hitherto unknown cerebral pyruvate recycling system assocd. with the tricarboxylic acid cycle, metabolizing primarily unlabeled acetyl-CoA, and (4) a predominant product of GABA in the glutamate compartment lacking glutamine synthase.
- 92Yoshimoto, M.; Waki, A.; Yonekura, Y.; Sadato, N.; Murata, T.; Omata, N.; Takahashi, N.; Welch, M. J.; Fujibayashi, Y. Characterization of acetate metabolism in tumor cells in relation to cell proliferation: Acetate metabolism in tumor cells. Nucl. Med. Biol. 2001, 28, 117– 122, DOI: 10.1016/S0969-8051(00)00195-5[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXisVWnt70%253D&md5=22030db3d8daf072e827f0d64fe0fddfCharacterization of acetate metabolism in tumor cells in relation to cell proliferation: Acetate metabolism in tumor cellsYoshimoto, M.; Waki, A.; Yonekura, Y.; Sadato, N.; Murata, T.; Omata, N.; Takahashi, N.; Welch, M. J.; Fujibayashi, Y.Nuclear Medicine and Biology (2001), 28 (2), 117-122CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)To reveal the metabolic fate of acetate in neoplasms that may characterize the accumulation patterns of [1-11C]acetate in tumors depicted by positron emission tomog. Four tumor cell lines (LS174T, RPMI2650, A2780, and A375) and fibroblasts in growing and resting states were used. In uptake expts., cells were incubated with[1-14C]acetate for 40 min. [14C]CO2 was measured in the tight-air chamber, and the metabolites in cells were identified by thin layer chromatog. and paper chromatog. The glucose metabolic rate of each cell line was measured with [2,6-3H]2-deoxy-glucose (DG), and the growth activity of each cell line was estd. by measuring the incorporation of [3H]methyl thymidine into DNA. Compared with resting fibroblasts, all four tumor cell lines showed higher accumulation of 14C activity from [1-14C]acetate. These tumor-to-normal ratios of [1-14C]acetate were larger than those of DG. Tumor cells incorporated 14C activity into the lipid-sol. fraction, mostly of phosphatidylcholine and neutral lipids, more prominently than did fibroblasts. The lipid-sol. fraction of 14C accumulation in cells showed a pos. correlation with growth activity, whereas the water-sol. and CO2 fractions did not. These findings suggest that the high tumor-to-normal ratio of [1-14C]acetate is mainly due to the enhanced lipid synthesis, which reflects the high growth activity of neoplasms. This in vitro study suggests that [1-11C]acetate is appropriate for estg. the growth activity of tumor cells.
- 93Dimitrakopoulou-Strauss, A.; Strauss, L. G. PET imaging of prostate cancer with 11C-acetate. J. Nucl. Med. 2003, 44, 556– 558[PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7mt1eltA%253D%253D&md5=2ee69d02682668a76370b56204ced5f7PET imaging of prostate cancer with 11C-acetateDimitrakopoulou-Strauss Antonia; Strauss Ludwig GJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2003), 44 (4), 556-8 ISSN:0161-5505.There is no expanded citation for this reference.
- 94Delbeke, D.; Pinson, C. W. 11C-Acetate: A new tracer for the evaluation of hepatocellular carcinoma. J. Nucl. Med. 2003, 44, 222– 223[PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252FmtFSktQ%253D%253D&md5=7d00cbc64489fa0095429746b59fdb5711C-acetate: a new tracer for the evaluation of hepatocellular carcinomaDelbeke Dominique; Pinson C WrightJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2003), 44 (2), 222-3 ISSN:0161-5505.There is no expanded citation for this reference.
- 95Mena, E.; Turkbey, B.; Mani, H.; Adler, S.; Valera, V. A.; Bernardo, M.; Shah, V.; Pohida, T.; McKinney, Y.; Kwarteng, G.; Daar, D.; Lindenberg, M. L.; Eclarinal, P.; Wade, R.; Linehan, W. M.; Merino, M. J.; Pinto, P. A.; Choyke, P. L.; Kurdziel, K. A. 11C-Acetate PET/CT in localized prostate cancer: A study with MRI and histopathologic correlation. J. Nucl. Med. 2012, 53, 538– 545, DOI: 10.2967/jnumed.111.096032[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvFaqu7w%253D&md5=564ca4ce96766df577b106b7f2eb27cd11C-acetate PET/CT in localized prostate cancer: a study with MRI and histopathologic correlationMena, Esther; Turkbey, Baris; Mani, Haresh; Adler, Stephen; Valera, Vladimir A.; Bernardo, Marcelino; Shah, Vijay; Pohida, Thomas; McKinney, Yolanda; Kwarteng, Gideon; Daar, Dagane; Lindenberg, Maria L.; Eclarinal, Philip; Wade, Revia; Linehan, W. Marston; Merino, Maria J.; Pinto, Peter A.; Choyke, Peter L.; Kurdziel, Karen A.Journal of Nuclear Medicine (2012), 53 (4), 538-545CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)This work characterizes the uptake of 11C-acetate in prostate cancer (PCa), benign prostate hyperplasia, and normal prostate tissue in comparison with multiparametric MRI, whole-mount histopathol., and clin. markers to evaluate the potential utility of 11C-acetate for delineating intraprostatic tumors in a population of patients with localized PCa. Methods: Thirty-nine men with presumed localized PCa underwent dynamic-static abdominal-pelvic 11C-acetate PET/CT for 30 min and 3-T multiparametric MRI before prostatectomy. PET/CT images were registered to MR images using pelvic bones for initial rotation-translation, followed by manual adjustments to account for prostate motion and deformation from the MRI endorectal coil. Whole-mount pathol. specimens were sectioned using an MRI-based patient-specific mold resulting in improved registration between the MRI, PET, and pathol. 11C-acetate PET standardized uptake values were compared with multiparametric MRI and pathol. Results: 11C-acetate uptake was rapid but reversible, peaking at 3-5 min after injection and reaching a relative plateau at approx. 10 min. The av. max. standardized uptake value (10-12 min) of tumors was significantly higher than that of normal prostate tissue (4.4 ± 2.05 [range, 1.8-9.2] vs. 2.1 ± 0.94 [range, 0.7-3.4], resp.; P < 0.001); however, it was not significantly different from that of benign prostatic hyperplasia (4.8 ± 2.01 [range, 1.8-8.8]). A sector-based comparison with histopathol., including all tumors greater than 0.5 cm, revealed a sensitivity and specificity of 61.6% and 80.0%, resp., for 11C-acetate PET/CT and 82.3% and 95.1 %, resp., for MRI. The 11C-acetate accuracy was comparable to that of MRI when only tumors greater than 0.9 cm were considered. In a small cohort (n = 9), 11C-acetate uptake was independent of fatty acid synthase expression using immunohistochem. Conclusion: 11C-acetate PET/CT demonstrates higher uptake in tumor foci than in normal prostate tissue; however, 11C-acetate uptake in tumors is similar to that in benign prostate hyperplasia nodules. Although 11C-acetate PET/CT is not likely to have utility as an independent modality for evaluation of localized PCa, the high uptake in tumors may make it useful for monitoring focal therapy when tissue damage after therapy may limit anat. imaging methods.
- 96Mohsen, B.; Giorgio, T.; Rasoul, Z. S.; Werner, L.; Ali, G. R. M.; Reza, D. K. V.; Ramin, S. Application of C-11-acetate positron-emission tomography (PET) imaging in prostate cancer: Systematic review and meta-analysis of the literature. BJU Int. 2013, 112, 1062– 1072, DOI: 10.1111/bju.12279[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslCgur%252FJ&md5=3f08b8d11ccc55d3f5d7a3a14d8f067bApplication of 11C-acetate positron-emission tomography (PET) imaging in prostate cancer: systematic review and meta-analysis of the literatureMohsen, Beheshti; Giorgio, Treglia; Rasoul, Zakavi Seyed; Werner, Langsteger; Ali, Ghodsi Rad Mohammad; Reza, Dabbagh Kakhki Vahid; Ramin, SadeghiBJU International (2013), 112 (8), 1062-1072CODEN: BJINFO; ISSN:1464-410X. (Wiley-Blackwell)To review the literature on the application of 11C-acetate positron-emission tomog. (PET) imaging in prostate cancer. We systematically reviewed the available literature and presented the results in meta-anal. format. PubMed, SCOPUS, ISI web of knowledge, Science Direct, Springer, and Google Scholar were searched with 'Acetate AND PET AND Prostate' as keywords. All studies that evaluated accuracy of 11C-acetate imaging in primary or recurrent prostate cancer were included, if enough data could be extd. for calcn. of sensitivity and/or specificity. In all, 23 studies were included in the study. For evaluation of primary tumor, pooled sensitivity was 75.1 (69.8-79.8)% and specificity was 75.8 (72.4-78.9)%. For detection of recurrence, sensitivity was 64 (59-69)% and specificity was 93 (83-98)%. Sensitivity for recurrence detection was higher in post-surgical vs post-radiotherapy patients and in patients with PSA at relapse of >1 ng/mL. Studies using PET/computed tomog. vs PET also showed higher sensitivity for detection of recurrence. Imaging with 11C-acetate PET can be useful in patients with prostate cancer. This is esp. true for evaluation of patients at PSA relapse, although the sensitivity is overall low. For primary tumor evaluation (localisation of tumor in the prostate and differentiation of malignant from benign lesions), 11C-acetate is of limited value due to low sensitivity and specificity. Due to the poor quality of the included studies, the results should be interpreted with caution and further high-quality studies are needed.
- 97Sandblom, G.; Sörensen, J.; Lundin, N.; Häggman, M.; Malmström, P.-U. Positron emission tomography with c11-acetate for tumor detection and localization in patients with prostate-specific antigen relapse after radical prostatectomy. Urology. 2006, 67, 996– 1000, DOI: 10.1016/j.urology.2005.11.044[Crossref], [PubMed], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD283ntVeruw%253D%253D&md5=486a7ee52aef9c38cf1d3ec53795ef26Positron emission tomography with C11-acetate for tumor detection and localization in patients with prostate-specific antigen relapse after radical prostatectomySandblom Gabriel; Sorensen Jens; Lundin Niclas; Haggman Michael; Malmstrom Per-UnoUrology (2006), 67 (5), 996-1000 ISSN:.OBJECTIVES: To evaluate positron emission tomography with C11-acetate as a method for detecting and localizing prostate cancer recurrence. No technique for localizing and detecting prostate cancer recurrence after biochemical relapse available today is sensitive enough to localize recurrence at a stage at which salvage radiotherapy is still curative. METHODS: Twenty patients (age 56 to 77 years) who had undergone radical prostatectomy and had an increasing prostate-specific antigen level measured on two consecutive occasions were included. In addition to the investigations usually performed when prostate cancer recurrence is suspected, they underwent positron emission tomography with C11-acetate as the marker. RESULTS: Pathologic uptake of acetate was seen in 15 (75%) of the 20 patients. In 8 of these patients, a solitary lesion was found (seven in the prostatic fossa and one at the regional lymph nodes). Multiple lesions were found in the remaining 7. False-positive uptake was seen in 3 men (15%). Additional investigations in these men revealed pathologic findings other than prostate cancer. CONCLUSIONS: Positron emission tomography with C11-acetate as marker is a promising method for early detection and localization of prostate cancer recurrence. False-positive uptake does occur.
- 98Haseebuddin, M.; Dehdashti, F.; Siegel, B. A.; Liu, J.; Roth, E. B.; Nepple, K. G.; Siegel, C. L.; Fischer, K. C.; Kibel, A. S.; Andriole, G. L.; Miller, T. R. 11C-Acetate PET/CT before radical prostatectomy: Nodal staging and treatment failure prediction. J. Nucl. Med. 2013, 54, 699– 706, DOI: 10.2967/jnumed.112.111153[Crossref], [PubMed], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosFCns7k%253D&md5=d858c827db240024c6ca641b5987008c11C-acetate PET/CT before radical prostatectomy: nodal staging and treatment failure predictionHaseebuddin, Mohammed; Dehdashti, Farrokh; Siegel, Barry A.; Liu, Jingxia; Roth, Elizabeth B.; Nepple, Kenneth G.; Siegel, Cary L.; Fischer, Keith C.; Kibel, Adam S.; Andriole, Gerald L.; Miller, Tom R.Journal of Nuclear Medicine (2013), 54 (5), 699-706CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)Despite early detection programs, many patients with prostate cancer present with intermediate- or high-risk disease. We prospectively investigated whether 11C-acetate PET/CT predicts lymph node (LN) metastasis and treatment failure in men for whom radical prostatectomy is planned. Methods: 107 men with intermediate- or high-risk localized prostate cancer and neg. conventional imaging findings underwent PET/CT with 11C-acetate. Five underwent LN staging only, and 102 underwent LN staging and prostatectomy. PET/CT findings were correlated with pathol. nodal status. Treatment-failure-free survival was estd. by the Kaplan-Meier method. The ability of PET/CT to predict outcomes was evaluated by multivariate Cox proportional hazards anal. Results: PET/CT was pos. for pelvic LN or distant metastasis in 36 of 107 patients (33.6%). LN metastasis was present histopathol. in 25 (23.4%). The sensitivity, specificity, and pos. and neg. predictive values of PET/CT for detecting LN metastasis were 68.0%, 78.1%, 48.6%, and 88.9%, resp. Treatment failed in 64 patients: 25 with metastasis, 17 with a persistent postprostatectomy prostate-specific antigen level greater than 0.20 ng/mL, and 22 with biochem. recurrence (prostate-specific antigen level > 0.20 ng/mL after nadir) during followup for a median of 44.0 mo. Treatment-failure-free survival was worse in PET-pos. than in PET-neg. patients (P < 0.0001) and in those with false-pos. than in those with true-neg. scan results (P < 0.01), suggesting that PET may have demonstrated nodal disease not removed surgically or identified pathol. PET positivity independently predicted failure in preoperative (hazard ratio, 3.26; P < 0.0001) and postoperative (hazard ratio, 3.07; P = 0.0001) multivariate models. Conclusion: In patients planned for or completing prostatectomy, 11C-acetate PET/CT detects LN metastasis not identified by conventional imaging and independently predicts treatment-failure-free survival.
- 99Leisser, A.; Pruscha, K.; Ubl, P.; Wadsak, W.; Mayerhöfer, M.; Mitterhauser, M.; Hacker, M.; Kramer, G.; Shariat, S.; Karanikas, G.; Hartenbach, M.; Haug, A. R. Evaluation of fatty acid synthase in prostate cancer recurrence: SUV of [11C]acetate PET as a prognostic marker. Prostate 2015, 75, 1760– 1767, DOI: 10.1002/pros.23061[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFOksLnI&md5=0506e30dbe2d0a5dbac9cad86ca52a52Evaluation of fatty acid synthase in prostate cancer recurrence: SUV of [11C]acetate PET as a prognostic markerLeisser, Asha; Pruscha, Konstatin; Ubl, Philipp; Wadsak, Wolfgang; Mayerhoefer, Marius; Mitterhauser, Markus; Hacker, Marcus; Kramer, Gero; Shariat, Shahrokh; Karanikas, Georgios; Hartenbach, Markus; Haug, Alexander R.Prostate (Hoboken, NJ, United States) (2015), 75 (15), 1760-1767CODEN: PRSTDS; ISSN:0270-4137. (Wiley-Blackwell)Aim: High levels of fatty acid synthase have shown to correlate with the aggressiveness of prostate cancer. As [11C]acetate exhibits a close correlation with the level of fatty acid synthase, we aimed to assess whether the SUV in [11C]acetate PET serves as a suitable prognostic marker in patients with recurrent prostate cancer. Materials and Methods: In 123 consecutive patients, examd. between 2010 and 2014, the max. standardized uptake value (SUVmax) of local recurrences as well as lymph node and bone metastases was measured. Choosing the spleen as a std. for relatively high physiol. uptake, a ratio of tumor to spleen uptake (SUVts) was calcd. for standardizing the uptake, too. The corresponding initial Gleason scores (GS) and serum-PSA levels around the time of the performed PET/CT for each patient were retrospectively collected and PSA doubling together with PSA velocity were detd. For further anal. patients were divided with regard to their initial Gleason score (≤3 + 4 and ≥ 4 + 3). The median of PSA velocity was calcd. to sep. patients with a high and low PSA velocity and Mann-Whitney U or Student's t-test were used, testing for significant differences. For correlation Spearmen-Rho test was used. Results : PET was pos. for recurrence in 82/123 patients. PSA was significantly higher in PET-pos. than in neg. patients (5.9 vs. 3.2 ng/mL; P = 0.006). Initial Gleason score did not differ in PET neg. and pos. patients (P = 0.3), whereas PSA velocity was markedly higher in PET pos. patients (0.4 vs. 0.1 ng/mL/mo; P = 0.01). Median SUVmax of PET pos. patients was 5.23 (mean 5.78; range 0.9-16.8) and median SUVts was 0.78 (mean 0.84, range 0.14-2.50). SUVts was significantly higher in patients with high PSA velocity (SUVts 0.76 vs. 0.92; P = 0.009), whereas SUVmax failed statistical significance (5.4 vs. 6.3 ng/mL/mo; P = 0.08). Patients with a high SUVmax proved to have a significantly higher median Gleason score compared to low uptake (8.0 vs. 7.0; P = 0.004). Vice versa both SUVmax (GS 6: 5.0; GS 7: 5.6; GS 8: 5.7; GS 9: 6.5; r = 0.30, P = 0.008) and SUVts (GS 6: 0.63; GS 7: 0.68; GS 8: 0.85; GS 9: 0.89; r = 0.30, P = 0.006) significantly correlated with Gleason score. Patients with a Gleason score ≤ 3 + 4 had a significantly lower SUVmax (4.8 vs. 5.7; P = 0.02) and SUVts (0.67 vs. 0.85; P = 0.02) as compared to a Gleason score ≥ 4 + 3. Conclusion: [11C]acetate uptake demonstrated to correlate with initial Gleason score. Furthermore, patients with a high PSA velocity proved to have higher [11C]acetate uptake in tumor lesions.
- 100Dusing, R. W.; Peng, W.; Lai, S.-M.; Grado, G. L.; Holzbeierlein, J. M.; Thrasher, J. B.; Hill, J.; Van Veldhuizen, P. J. Prostate-specific antigen and prostate-specific antigen velocity as threshold indicators in 11C-Acetate PET/CTAC scanning for prostate cancer recurrence. Clinical Nuclear Medicine. 2014, 39, 777– 783, DOI: 10.1097/RLU.0000000000000516[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cbjtlKktA%253D%253D&md5=3caf04b61f8575e4c33452e5560f040fProstate-specific antigen and prostate-specific antigen velocity as threshold indicators in 11C-acetate PET/CTAC scanning for prostate cancer recurrenceDusing Reginald W; Peng Warner; Lai Sue-Min; Grado Gordon L; Holzbeierlein Jeffrey M; Thrasher J Brantley; Hill Jacqueline; Van Veldhuizen Peter JClinical nuclear medicine (2014), 39 (9), 777-83 ISSN:.PURPOSE: The aim of this study was to identify which patient characteristics are associated with the highest likelihood of positive findings on 11C-acetate PET/computed tomography attenuation correction (CTAC) (PET/CTAC) scan when imaging for recurrent prostate cancer. METHODS: From 2007 to 2011, 250 11C-acetate PET/CTAC scans were performed at a single institution on patients with prostate cancer recurrence after surgery, brachytherapy, or external beam radiation. Of these patients, 120 met our inclusion criteria. Logistic regression analysis was used to examine the relationship between predictability of positive findings and patients' characteristics, such as prostate-specific antigen (PSA) level at the time of scan, PSA kinetics, Gleason score, staging, and type of treatment before scan. RESULTS: In total, 68.3% of the 120 11C-acetate PET/CTAC scans were positive. The percentage of positive scans and PSA at the time of scanning and PSA velocity (PSAV) had positive correlations. The putative sensitivity and specificity were 86.6% and 65.8%, respectively, when a PSA level greater than 1.24 ng/mL was used as the threshold for scanning. The putative sensitivity and specificity were 74% and 75%, respectively, when a PSAV level greater than 1.32 ng/mL/y was used as the threshold. No significant associations were found between scan positivity and age, PSA doubling time, Gleason score, staging, or type of treatment before scanning. CONCLUSIONS: This retrospective study suggests that threshold models of PSA greater than 1.24 ng/mL or PSAV greater than 1.32 ng/mL per year are independent predictors of positive findings in 11C-acetate PET/CTAC imaging of recurrent prostate cancer.
- 101Yamamoto, Y.; Nishiyama, Y.; Kimura, N.; Kameyama, R.; Kawai, N.; Hatakeyama, T.; Kaji, M.; Ohkawa, M. 11C-acetate PET in the evaluation of brain glioma: Comparison with 11C-methionine and 18F-FDG-PET. Mol. Imaging Biol. 2008, 10, 281– 287, DOI: 10.1007/s11307-008-0152-5[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cvpvVygtQ%253D%253D&md5=99af6ee173c61346e47b54d73546e7cb11C-acetate PET in the evaluation of brain glioma: comparison with 11C-methionine and 18F-FDG-PETYamamoto Y; Nishiyama Y; Kimura N; Kameyama R; Kawai N; Hatakeyama T; Kaji M; Ohkawa MMolecular imaging and biology (2008), 10 (5), 281-7 ISSN:1536-1632.PURPOSE: The aim of the study is to retrospectively investigate the usefulness of 11C-acetate (ACE)-positron emission tomography (PET) for evaluation of brain glioma, in comparison with 11C-methionine (MET) and 2-deoxy-2-18F-fluoro-D-glucose (FDG). PROCEDURES: Fifteen patients with brain glioma referred to initial diagnosis were examined with ACE, MET, and FDG-PET. Five patients had low-grade gliomas (grade II), three had anaplastic astrocytomas (grade III), and seven had glioblastomas (grade IV). PET results were evaluated by visual and semiquantitative analysis. For semiquantitative analysis, the standardized uptake value (SUV) and tumor to contralateral normal gray matter (T/N) ratio were calculated. The sensitivity for detection of high-grade gliomas was calculated using visual analysis. RESULTS: Sensitivities of ACE, MET, and FDG were 90%, 100%, and 40%, respectively. ACE and MET T/N ratios were significantly higher than that of FDG. ACE and FDG SUV in high-grade gliomas were significantly higher than that in low-grade gliomas. No significant differences were observed using MET. CONCLUSIONS: ACE PET is a potentially useful radiotracer for detecting brain gliomas and differentiating high-grade gliomas.
- 102Tsuchida, T.; Takeuchi, H.; Okazawa, H.; Tsujikawa, T.; Fujibayashi, Y. Grading of brain glioma with 1–11C-acetate PET: Comparison with 18F-FDG PET. Nucl. Med. Biol. 2008, 35, 171– 176, DOI: 10.1016/j.nucmedbio.2007.11.004[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsl2hurw%253D&md5=263040fa88e157272910a38445bf81acGrading of brain glioma with 1-11C-acetate PET: comparison with 18F-FDG PETTsuchida, Tatsuro; Takeuchi, Hiroaki; Okazawa, Hidehiko; Tsujikawa, Tetsuya; Fujibayashi, YasuhisaNuclear Medicine and Biology (2008), 35 (2), 171-176CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)The objective of this study is to reevaluate the clin. significance of 1-11C-acetate (ACE) positron emission tomog. (PET) in patients with brain glioma, in comparison with 18F-fluorodeoxyglucose (FDG) PET. Methods: Ten patients with histol. proven glioma were included in this study. They underwent PET examn. with both FDG and ACE on sep. days. For ACE PET, 20-min data acquisition was performed just after the administration of 740 MBq of ACE; 10-20-min data were used for the anal. FDG PET data acquisition for 10 min started 60 min postinjection of 370 MBq of FDG, approx. Both reconstructed images were converted to standardized uptake value (SUV) images for patient body wt. and injected dose. Regions of interest were placed on the tumor and the contralateral cerebral cortex, and SUV and tumor-to-cortex ratio (T/C) were calcd.; these values were compared between high- and low-grade gliomas. Results: SUV and T/C of ACE PET showed significant difference (SUV: 2.63±0.46 vs. 1.85±0.56, P =.03; T/C: 2.36±0.63 vs. 1.14±0.36, P =.02). In contrast, FDG PET revealed no significant difference in SUV or T/C between high- and low-grade gliomas (SUV: 7.13±4.31 vs. 4.71±1.27, P =.31; T/C: 0.98±0.55 vs. 0.62±0.09, P =.22). Conclusion: This preliminary study revealed that ACE PET is a promising tracer for the grading of brain glioma.
- 103Kim, S.; Kim, D.; Kim, S. H.; Park, M.; Chang, J. H.; Yun, M. The roles of 11C-acetate PET/CT in predicting tumor differentiation and survival in patients with cerebral glioma. Eur. J. Nucl. Med. Mol. Imaging 2018, 45, 1012– 1020, DOI: 10.1007/s00259-018-3948-9[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MrosVSntw%253D%253D&md5=a6a6c103f8e0de500f6bb0f910ba47a3The roles of (11)C-acetate PET/CT in predicting tumor differentiation and survival in patients with cerebral gliomaKim Soyoung; Kim Dongwoo; Yun Mijin; Kim Se Hoon; Park Mi-Ae; Chang Jong HeeEuropean journal of nuclear medicine and molecular imaging (2018), 45 (6), 1012-1020 ISSN:.PURPOSE: This prospective study aimed to evaluate the clinical values of (11)C-acetate positron emission tomography/computed tomography (PET/CT) in predicting histologic grades and survival in patients with cerebral glioma. METHODS: Seventy-three patients with surgically confirmed cerebral gliomas (19 grade II, 21 grade III, and 33 grade IV) who underwent (11)C-acetate PET/CT before surgery were included. Tumor-to-choroid plexus ratio (TCR), which was defined as the maximum standardized uptake value (SUV) of tumors to the mean SUV of choroid plexus, was compared between three World Health Organization (WHO) grade groups. Moreover, metabolic tumor volumes (MTV) were calculated. Progression-free survival (PFS) and overall survival (OS) curves were plotted using the Kaplan-Meier method, and differences in survival between groups were assessed using the log-rank test. RESULTS: Median TCR was 1.20 (interquartile range [IQR], 1.14 to 1.4) in grade II, 1.65 (IQR, 1.26 to 1.79) in grade III, and 2.53 (IQR, 1.93 to 3.30) in grade IV gliomas. Significant differences in TCR were seen among the three WHO grade groups (P < 0.001). In Cox regression analysis including TCR, MTV, molecular markers, and other clinical factors, TCR was prognostic for PFS (P = 0.016) and TCR and MTV were prognostic for OS (P = 0.024 [TCR], P = 0.030 [MTV]). PFS and OS were significantly shorter in patients with a TCR ≥ 1.6 than in those with a TCR < 1.6. OS were significantly shorter in patients with a MTV ≥ 1 than in those with a TCR < 1. CONCLUSIONS: TCR on (11)C-acetate PET/CT significantly differed between low- and high-grade cerebral gliomas, and it showed the capability to further differentiate grade III from grade IV tumors. TCR and MTV were independent prognostic factors and predicted survival better than did the WHO grade.
- 104Christman, D.; Crawford, E. J.; Friedkin, M.; Wolf, A. P. Detection of DNA synthesis in intact organisms with positron-emitting [methyl-11C]thymidine. Proc. Natl. Acad. Sci. U. S. A. 1972, 69, 988– 992, DOI: 10.1073/pnas.69.4.988[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38XktVanurc%253D&md5=95954ed3e383e2f46bf41c99f0715817Detection of DNA synthesis in intact organisms with positron-emitting [methyl-11C]-thymidineChristman, David; Crawford, Elizabeth J.; Friedkin, Morris; Wolf, Alfred P.Proceedings of the National Academy of Sciences of the United States of America (1972), 69 (4), 988-92CODEN: PNASA6; ISSN:0027-8424.1CO2 produced in the Brookhaven 152-cm cyclotron was converted to CH2O, which in turn was used for the enzymic conversion of deoxyuridine-5'-phosphate to thymidylate-11C (I). Enzymic treatment of the nucleotide with alk. phosphatase gave thymidine-11C (II). The prepn. of II from cyclotron-generated 11CO2 required 110 min (about 5 half-lives): 35 min for the synthesis of 11CH2O, 25 min for the enzymic conversion to I, 20 min for column chromatog., 5 min for phosphatase treatment, 10 min for evapn., 2 min for filtration through an anion-exchange resin, and 13 min for misc. manipulations. Positron-emitting II and I were used for in vivo tracer studies of DNA synthesis in mice for periods of up to 3 hr. Findings with 11C were consistent with earlier studies in which 14C and 3H-labeled thymidine were used.
- 105Wells, P.; Gunn, R. N.; Alison, M.; Steel, C.; Golding, M.; Ranicar, A. S.; Brady, F.; Osman, S.; Jones, T.; Price, P. Assessment of proliferation in vivo using 2-[(11)C]thymidine positron emission tomography in advanced intra-abdominal malignancies. Cancer Res. 2002, 62, 5698– 5702[PubMed], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotFyksbo%253D&md5=53aab8620638a24d9ad0351c7d23f1bcAssessment of proliferation in vivo using 2-[11C]thymidine positron emission tomography in advanced intra-abdominal malignanciesWells, Paula; Gunn, Roger N.; Alison, Malcolm; Steel, Colin; Golding, Mathew; Ranicar, Alex S.; Brady, Frank; Osman, Safiye; Jones, Terry; Price, PatCancer Research (2002), 62 (20), 5698-5702CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The purpose of this study was to det. the relationship between 2-[11C]thymidine positron emission tomog. (PET) in vivo-derived parameters and the ex vivo Ki-67 index of proliferation in human tumors. The study comprised 17 treatment-naive patients with advanced intra-abdominal malignancies. Tumor thymidine kinetics were measured using 2-[11C]thymidine PET. Tissue data were analyzed to give the standardized uptake value, the area under the time activity curve, and the fractional retention of thymidine (FRT) obtained by kinetic modeling. For the latter, the contribution of labeled metabolites was accounted for by measuring thymidine metabolites in arterial plasma. To examine the influence of tumor blood flow on the thymidine PET data, a perfusion scan using inhaled [15O]CO2 was carried out in a subset of 11 patients. Biopsies were stained with a MIB1 antibody to obtain a Ki-67 index, and correlations with the PET-derived parameters were investigated. There was no relationship between tumor blood flow and the thymidine PET data, showing that the retention of 2-[11C]thymidine in tumors was independent of tumor perfusion. There was no correlation between the Ki-67 index and either std. uptake value or area under the curve. There was a correlation between the Ki-67 index and FRT (r = 0.58; P = 0.01). The correlation between the Ki-67 index and FRT in this dataset was not influenced by the interval between biopsy and imaging (0.1-126 wk), the origin of the biopsy for Ki-67 staining (primary tumor or metastasis), or whether the biopsy was from an imaged or a nonimaged tumor. This is the first report in human tumors showing that 2-[11C]thymidine PET-derived parameters correlate with the level of tumor proliferation measured using Ki-67 immunohistochem. The study shows that the in vivo measurement of 2-[11C]thymidine in tumors using PET can provide a surrogate marker of proliferation and supports the potential use of the technique in the early assessment of response to antiproliferative cancer treatment.
- 106Barwick, T.; Bencherif, B.; Mountz, J. M.; Avril, N. Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: A comprehensive evaluation. Nucl. Med. Commun. 2009, 30, 908– 917, DOI: 10.1097/MNM.0b013e32832ee93b[Crossref], [PubMed], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1SltbnL&md5=5e4c6c8a38cd0e0577d78e85c769ba5dMolecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluationBarwick, Tara; Bencherif, Badreddine; Mountz, James M.; Avril, NorbertNuclear Medicine Communications (2009), 30 (12), 908-917CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)A review. Positron emission tomog. (PET) using F-18 fluoro-3'-deoxy-3-L-fluorothymidine (FLT) offers noninvasive assessment of cell proliferation in vivo. The most important application refers to the evaluation of tumor proliferative activity, representing a key feature of malignancy. Most data to date suggest that FLT is not a suitable biomarker for staging of cancers. This is because of the rather low fraction of tumor cells that undergo replication at a given time with subsequently relatively low tumor FLT uptake. In addn., generally, the high FLT uptake in liver and bone marrow limits the diagnostic use. We describe the current status on preclin. and clin. applications of FLT-PET including our own experience in brain tumors. The future of FLT-PET probably lies in the evaluation of tumor response to therapy and more importantly, in the prediction of early response in the course of treatment. The level of FLT accumulation in tumors depends on thymidine kinase 1 activity and on the therapy-induced activation of the salvage pathway and expression of nucleoside transporters. Therefore, cytostatic agents that cause arrest of the cell cycle in the S-phase may initially increase FLT uptake rather than reducing the tumor cell accumulation. In addn., agents that block the endogenous thymidine pathway may lead to overactivity of the salvage pathway and increase tumor FLT uptake. In contrast, many therapeutic agents inhibit both pathways and subsequently reduce tumor FLT uptake. Further studies comparing FLT with F-18 fluorodeoxyglucose-PET will be important to det. the complementary advantage of FLT-PET in early cancer therapy response assessment. Further research should be facilitated by simplified synthesis of FLT with improved yields and an increasing com. availability.
- 107Conti, P. S.; Alauddin, M. M.; Fissekis, J. R.; Schmall, B.; Watanabe, K. A. Synthesis of 2′-fluoro-5-[11C]-methyl-1-β-d-arabinofuranosyluracil ([11C]-FMAU): A potential nucleoside analog for in vivo study of cellular proliferation with PET. Nucl. Med. Biol. 1995, 22, 783– 789, DOI: 10.1016/0969-8051(95)00017-R[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXos1ChsLw%253D&md5=3a594ac09c35247304ebc6e2f763eb492'-fluoro-5-[11C]-methyl-1-β-d-arabinofuranosyluracil ([11C]-FMAU): a potential nucleoside analog for in vivo study of cellular proliferation with PETConti, Peter S.; Alauddin, Mian M.; Fissekis, John R.; Schmall, Bernard; Watanabe, Kyochi A.Nuclear Medicine and Biology (1995), 22 (6), 783-9CODEN: NMBIEO; ISSN:0883-2897. (Elsevier)Rapid in vivo catabolism limits the use of currently available radiotracers used in tumor proliferation studies with positron emission tomog. (PET). This is manifested by the need to develop complex math. models to interpret kinetic and metabolite data obtained from imaging studies with agents such as carbon-11 labeled thymidine. A potential carbon-11 labeled radiotracer for cellular proliferation, 2'-fluoro-5-([11C]-methyl)-1-β-D-arabinofuranosyluracil (FMAU), has been prepd. using a previously described method for prepn. of [11C]methyl-thymidine where selective alkylation of a pyrimidyl dianion is accomplished with [11C]methyl iodide at the 5-position of the pyrimidine ring. FMAU shares many in vivo characteristics of thymidine, including cellular transport, phosphorylation by mammalian kinase, and incorporation into DNA. Most importantly, in vivo catabolism of FMAU is limited, potentially yielding simplified kinetic models for detn. of cellular proliferation with positron emission tomog.
- 108Conti, P. S.; Bading, J. R.; Mouton, P. P.; Links, J. M.; Alauddin, M. M.; Fissekis, J. D.; Ravert, H. T.; Hilton, J.; Wong, D. F.; Anderson, J. H. In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET. Nucl. Med. Biol. 2008, 35, 131– 141, DOI: 10.1016/j.nucmedbio.2007.09.003[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVOlt7zO&md5=4189b8f346ad659be7b4414204443605In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PETConti, Peter S.; Bading, James R.; Mouton, Peter P.; Links, Jonathan M.; Alauddin, Mian M.; Fissekis, John D.; Ravert, Hayden T.; Hilton, John; Wong, Dean F.; Anderson, James H.Nuclear Medicine and Biology (2008), 35 (1), 131-141CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)Introduction: Noncatabolized thymidine analogs are being developed for use in imaging DNA synthesis. We sought to relate a labeling index measured by immunohistochem. staining bromodeoxyuridine (BUdR) technique to the uptake of 11C 2'-fluoro-5-methyl-1-β-D-arabinofuranosyluracil (FMAU) measured with positron emission tomog. (PET) in a brain tumor model. Methods: Adult beagles (n = 8) with implanted brain tumors received [11C]FMAU and dynamic imaging with arterial sampling. Six dogs were then infused with BUdR (200 mg/m2) and sacrificed. Tumor time-activity curves (TACs) obtained from computed-tomog.-defined regions of interest were cor. for partial vol. effects and crosstalk from brain tissue. Tissue was analyzed for the percentage of tumor vol. occupied by viable cells and by viable cells in S-phase as identified by BUdR staining. PET/[11C]FMAU and BUdR were compared by linear regression anal. and anal. of variance, as well as by a nonparametric rank correlation test. Results: Tumor standardized uptake values (SUVs) and tumor-to-contralateral-brain uptake ratios at 50 min were 1.6±0.4 and 5.5±1.2 (n = 8; mean ± S.E.M.), resp. No 11C-labeled metabolites were obsd. in the blood through 60 min. Tumor TACs were well described with a three-compartment/four-parameter model (k4 = 0) and by Patlak anal. Parametric statistical anal. showed that FMAU clearance from plasma into tumor compartment 3 (KFMAU) was significantly correlated with S-phase percent vol. (P =.03), while tumor SUV was significantly correlated with both S-phase percent vol. and cell percent vol. (P =.02 and.03, resp.). Patlak slope, KFMAU and tumor SUV were equiv. with regard to rank correlation anal., which showed that tumor uptake and trapping of FMAU were correlated with the vol. d. of dividing cells (P =.0003) rather than nondividing cells (P =.3). Conclusions: Trapping of [11C]FMAU correlated with tumor growth rate, as measured by direct tissue anal. with BUdR in a canine brain tumor model, suggesting that [11C]FMAU is useful for the imaging of cell proliferation in cancers.
- 109Shields, A. F. PET imaging with 18F-FLT and thymidine analogs: Promise and pitfalls. J. Nucl. Med. 2003, 44, 1432– 1434[PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVSrt74%253D&md5=fdffb85db8a9f44c9aef7da723df9e46PET imaging with 18F-FLT and thymidine analogs: promise and pitfallsShields, Anthony F.Journal of Nuclear Medicine (2003), 44 (9), 1432-1434CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review on imaging of cellular proliferation in tumors with 18F-labeled 3'-deoxy-3'fluorothymidine (18F-FLT) and thymidine analogs using positron emission tomog. (PET).
- 110Toyohara, J. Evaluation of DNA synthesis with carbon-11-labeled 4′-thiothymidine. WJR. 2016, 8, 799– 808, DOI: 10.4329/wjr.v8.i9.799
- 111Nariai, T.; Inaji, M.; Sakata, M.; Toyohara, J. Use of 11C-4DST-PET for Imaging of Human Brain Tumors. In Tumors of the Central Nervous System, Vol. 11; Hayat, M. A., Ed.; Tumors of the Central Nervous System; Springer Netherlands: Dordrecht, The Netherlands, 2014; Vol. 11, pp 41– 48.
- 112Toyota, Y.; Miyake, K.; Kawai, N.; Hatakeyama, T.; Yamamoto, Y.; Toyohara, J.; Nishiyama, Y.; Tamiya, T. Comparison of 4′-[methyl-11C]thiothymidine (11C-4DST) and 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) PET/CT in human brain glioma imaging. EJNMMI Res. 2015, 5, 7, DOI: 10.1186/s13550-015-0085-3[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mjit1Wjug%253D%253D&md5=ebb2a3b02785d5e9875738c1f09abdc1Comparison of 4'-[methyl-(11)C]thiothymidine ((11)C-4DST) and 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) PET/CT in human brain glioma imagingToyota Yasunori; Miyake Keisuke; Kawai Nobuyuki; Hatakeyama Tetsuhiro; Tamiya Takashi; Yamamoto Yuka; Nishiyama Yoshihiro; Toyohara JunEJNMMI research (2015), 5 (), 7 ISSN:2191-219X.BACKGROUND: 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) has been used to evaluate tumor malignancy and cell proliferation in human brain gliomas. However, (18)F-FLT has several limitations in clinical use. Recently, (11)C-labeled thymidine analogue, 4'-[methyl-(11)C]thiothymidine ((11)C-4DST), became available as an in vivo cell proliferation positron emission tomography (PET) tracer. The present study was conducted to evaluate the usefulness of (11)C-4DST PET in the diagnosis of human brain gliomas by comparing with the images of (18)F-FLT PET. METHODS: Twenty patients with primary and recurrent brain gliomas underwent (18)F-FLT and (11)C-4DST PET scans. The uptake values in the tumors were evaluated using the maximum standardized uptake value (SUVmax), the tumor-to-normal tissue uptake (T/N) ratio, and the tumor-to-blood uptake (T/B) ratio. These values were compared among different glioma grades. Correlation between the Ki-67 labeling index and the uptake values of (11)C-4DST and (18)F-FLT in the tumor was evaluated using linear regression analysis. The relationship between the individual (18)F-FLT and (11)C-4DST uptake values in the tumors was also examined. RESULTS: (11)C-4DST uptake was significantly higher than that of (18)F-FLT in the normal brain. The uptake values of (11)C-4DST in the tumor were similar to those of (18)F-FLT resulting in better visualization with (18)F-FLT. No significant differences in the uptake values of (18)F-FLT and (11)C-4DST were noted among different glioma grades. Linear regression analysis showed a significant correlation between the Ki-67 labeling index and the T/N ratio of (11)C-4DST (r = 0.50, P < 0.05) and (18)F-FLT (r = 0.50, P < 0.05). Significant correlations were also found between the Ki-67 labeling index and the T/B ratio of (11)C-4DST (r = 0.52, P < 0.05) and (18)F-FLT (r = 0.55, P < 0.05). A highly significant correlation was observed between the individual T/N ratio of (11)C-4DST and (18)F-FLT in the tumor (r = 0.79, P = 0.0001). CONCLUSIONS: The present study demonstrates that (11)C-4DST is useful for the imaging of human brain gliomas with PET. A relatively higher background uptake of (11)C-4DST in the normal brain compared to (18)F-FLT limits the detection of low-tracer-uptake tumors. Moreover, no superiority was found in (11)C-4DST over (18)F-FLT in the evaluation of cell proliferation.
- 113Tanaka, K.; Yamamoto, Y.; Maeda, Y.; Yamamoto, H.; Kudomi, N.; Kawai, N.; Toyohara, J.; Nishiyama, Y. Correlation of 4′-[methyl-11C]-thiothymidine uptake with Ki-67 immunohistochemistry and tumor grade in patients with newly diagnosed gliomas in comparison with 11C-methionine uptake. Ann. Nucl. Med. 2016, 30, 89– 96, DOI: 10.1007/s12149-015-1035-x[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslersr7J&md5=66a526982a6b5b762c23608a3f9bae78Correlation of 4'-[methyl-11C]-thiothymidine uptake with Ki-67 immunohistochemistry and tumor grade in patients with newly diagnosed gliomas in comparison with 11C-methionine uptakeTanaka, Kenichi; Yamamoto, Yuka; Maeda, Yukito; Yamamoto, Hiroyuki; Kudomi, Nobuyuki; Kawai, Nobuyuki; Toyohara, Jun; Nishiyama, YoshihiroAnnals of Nuclear Medicine (2016), 30 (2), 89-96CODEN: ANMEEX; ISSN:0914-7187. (Springer Japan)A novel radiopharmaceutical, 4'-[methyl-11C]thiothymidine (11C-4DST), has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate 11C-4DST uptake in patients with newly diagnosed glioma and to correlate the results with proliferative activity and tumor grade, in comparison with L-[methyl-11C]-methionine (11C-MET). Investigations of 11C-4DST and 11C-MET PET/CT were performed retrospectively in 23 patients with newly diagnosed glioma. The max. standardized uptake value (SUVmax) for tumor (T) and the mean SUV for normal contralateral hemisphere (N) were calcd., and the tumor-to-normal (T/N) ratio was detd. Metabolic tumor vol. (MTV) was defined as the vol. with a threshold of 40% of the SUVmax. Proliferative activity as indicated by the Ki-67 index was estd. in tissue specimens. Of 23 gliomas examd., 11C-4DST PET/CT and 11C-MET PET/CT detected 20 and 22, resp. Linear regression anal. between 11C-4DST and 11C-MET indicated a weak correlation for SUVmax (r = 0.54, P < 0.008), for T/N ratio (r = 0.56, P < 0.006), and for MTV (r = 0.60, P < 0.003). Linear regression anal. indicated a weak correlation between 11C-4DST and Ki-67 index for SUVmax (r = 0.46, P < 0.03), for T/N ratio (r = 0.43, P < 0.05), and for MTV (r = 0.68, P < 0.001) and between 11C-MET MTV and Ki-67 index (r = 0.43, P < 0.04). Using 11C-4DST, there was a significant difference in SUVmax between grades II and IV (P < 0.03) and in MTV between grades II and IV (P < 0.009) and grades III and IV (P < 0.02). Using 11C-MET, there was a significant difference in SUVmax (P < 0.009) and T/N ratio (P < 0.02) between grades II and IV and in MTV between grades II and IV (P < 0.03) and grades III and IV (P < 0.02). A11C-4DST PET/CT is feasible for imaging of brain gliomas, as well as 11C-MET PET/CT. Esp., it showed the highest correlation coeff. between 11C-4DST MTV and Ki-67 index in newly diagnosed gliomas.
- 114Ito, K.; Yokoyama, J.; Miyata, Y.; Toyohara, J.; Okasaki, M.; Minamimoto, R.; Morooka, M.; Ishiwata, K.; Kubota, K. Volumetric comparison of positron emission tomography/computed tomography using 4′-[methyl-11C]-thiothymidine with 2-deoxy-2–18F-fluoro-D-glucose in patients with advanced head and neck squamous cell carcinoma. Nucl. Med. Commun. 2015, 36, 219– 225, DOI: 10.1097/MNM.0000000000000241[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVOhtr4%253D&md5=a7943d28c1676d2e2b65f338fdff54ecVolumetric comparison of positron emission tomography/computed tomography using 4'-[methyl-11C]-thiothymidine with 2-deoxy-2-18F-fluoro-D-glucose in patients with advanced head and neck squamous cell carcinomaIto, Kimiteru; Yokoyama, Junkichi; Miyata, Yoko; Toyohara, Jun; Okasaki, Momoko; Minamimoto, Ryogo; Morooka, Miyako; Ishiwata, Kiichi; Kubota, KazuoNuclear Medicine Communications (2015), 36 (3), 219-225CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)Objective: We prospectively compared the diagnostic value of PET/computed tomog. (CT) findings using the tracers 4'-[methyl-C]-thiothymidine (C-4DST) and 2-deoxy-2-F-fluoro-D-glucose (F-FDG) in patients with head and neck squamous cell carcinoma (HNSCC). Patients and methods: Thirty-eight patients with advanced HNSCC underwent C-4DST PET/CT and F-FDG PET/CT before treatment. Maximum standardized uptake values (SUVmax) were measured for both PET/CT studies; in addn., total lesion glycolysis (TLG) of F-FDG PET/CT and total lesion proliferation (TLP) of C-4DST PET/CT were measured. Abs. TLG and TLP values as well as values with various SUV thresholds were measured. All patients were followed up for 13.5±7.5 mo (mean±SD) to monitor recurrence. Results: A statistically significant correlation was obsd. between the primary tumor SUVmax for C-4DST PET/CT and F-FDG PET/CT (r=0.46, P<0.01). TLP values with SUV thresholds strongly correlated with TLG values relative to the same thresholds (r=0.60-0.92, P<0.001). Nine of the 38 patients with post-treatment recurrence were identified. Receiver operating characteristic curves for TLG3.0 and TLP2.5 showed the highest prognostic ability for recurrence; the sensitivity and specificity of TLG3.0 were 89 and 72%, resp., and the sensitivity and specificity of TLP2.5 were 89 and 55%, resp. Conclusion: In patients with advanced HNSCC, the TLP of C-4DST PET/CT strongly correlated with the TLG of F-FDG PET/CT. Although there were no large differences between these values, the receiver operating characteristic curves of the abs. TLG had slightly better prognostic ability for recurrence.
- 115Minamimoto, R.; Toyohara, J.; Ito, H.; Seike, A.; Miyata, Y.; Morooka, M.; Okasaki, M.; Nakajima, K.; Ito, K.; Ishiwata, K.; Kubota, K. A pilot study of 4′-[methyl-11C]-thiothymidine PET/CT for detection of regional lymph node metastasis in non-small cell lung cancer. EJNMMI Res. 2014, 4, 10, DOI: 10.1186/2191-219X-4-10[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crgslKhsA%253D%253D&md5=1e53d6912c4225449e09a2dbb3ebaf32A pilot study of 4'-[methyl-11C]-thiothymidine PET/CT for detection of regional lymph node metastasis in non-small cell lung cancerMinamimoto Ryogo; Toyohara Jun; Ito Hideyuki; Seike Ayako; Miyata Yoko; Morooka Miyako; Okasaki Momoko; Nakajima Kazuhiko; Ito Kimiteru; Ishiwata Kiichi; Kubota KazuoEJNMMI research (2014), 4 (1), 10 ISSN:2191-219X.BACKGROUND: 4'-[methyl-11C]-thiothymidine (4DST) is a novel positron emission tomography (PET) tracer to assess proliferation of malignancy. The diagnostic abilities of 4DST and 2-deoxy-2-18 F-fluoro-d-glucose (FDG) for detecting regional lymph node (LN) metastases of non-small cell lung cancer (NSCLC) were prospectively compared. In addition, the relationship between the PET result and the patient's prognosis was evaluated. METHODS: A total of 31 patients with NSCLC underwent 4DST PET/computed tomography (CT) and FDG PET/CT. The PET/CT images were evaluated qualitatively and quantitatively for focal uptake of each PET tracer, according to the staging system of the American Joint Committee on Cancer. Surgical and histological results provided the reference standards. Patients were followed for up to two years to assess disease-free survival. RESULTS: On a per-lesion basis, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for LN staging were 82%, 72%, 32%, 96%, and 73%, respectively, for 4DST, and 29%, 86%, 25%, 88%, and 78%, respectively, for FDG. The sensitivity of 4DST was significantly higher than that of FDG (P < 0.001). The disease-free survival rate with positive 4DST uptake in nodal lesions was 0.35, which was considerably lower than the rate of 0.83 with negative findings (P = 0.04). Among the factors tested, nodal staging by 4DST was the most influential prognostic factor (P = 0.05) in predicting the presence of a previously existing spread lesion or of a recurrence over the course of 2 years. CONCLUSION: 4DST PET/CT is sensitive for detecting mediastinal lymph node metastasis in NSCLC, but its low specificity is a limitation. However, it may be helpful in predicting the prognosis of NSCLC.
- 116Okasaki, M.; Kubota, K.; Minamimoto, R.; Miyata, Y.; Morooka, M.; Ito, K.; Ishiwata, K.; Toyohara, J.; Inoue, T.; Hirai, R.; Hagiwara, S.; Miwa, A. Comparison of 11C-4′-thiothymidine, 11C-methionine, and 18F-FDG PET/CT for the detection of active lesions of multiple myeloma. Ann. Nucl. Med. 2015, 29, 224– 232, DOI: 10.1007/s12149-014-0931-9[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFyjsb%252FJ&md5=cfb8e29285ae78b8734444285dc445ceComparison of 11C-4'-thiothymidine, 11C-methionine, and 18F-FDG PET/CT for the detection of active lesions of multiple myelomaOkasaki, Momoko; Kubota, Kazuo; Minamimoto, Ryogo; Miyata, Yoko; Morooka, Miyako; Ito, Kimiteru; Ishiwata, Kiichi; Toyohara, Jun; Inoue, Tomio; Hirai, Risen; Hagiwara, Shotaro; Miwa, AkiyoshiAnnals of Nuclear Medicine (2015), 29 (3), 224-232CODEN: ANMEEX; ISSN:0914-7187. (Springer Japan)Purpose: The aims of this study were to evaluate the possibility of using 11C-methionine (11C-MET) and 11C-4'-thiothymidine (11C-4DST) whole-body PET/CT for the imaging of amino acid metab. and DNA synthesis, resp., when searching for bone marrow involvement in patients with multiple myeloma (MM) and to compare these findings with those for 18F-FDG PET/CT and aspiration cytol. Methods: A total of 64 patients with MM, solitary plasmacytoma, monoclonal gammopathy of undetd. significance, or an unspecified diagnosis were prospectively enrolled. All the patients underwent three whole-body PET/CT examns. within a period of 1 wk. First, the tracer accumulation was visually evaluated as pos., equivocal, or neg. for 55 focal lytic lesions visualized using CT in 24 patients. Second, the percentages of marrow plasma cells as calcd. using a bone marrow aspiration smear and tracer accumulation were evaluated in the posterior iliac crests of 36 patients. Results: Among the 55 lytic lesions, the 11C-MET and 11C-4DST findings tended to reveal more pos. findings than the 18F-FDG findings. Based on the std. criteria for the diagnosis of active myeloma using the percentage of marrow plasma cells, significant differences were found between the 18F-FDG and 11C-MET findings and between the 18F-FDG and 11C-4DST findings, but no significant difference was obsd. between the 11C-MET and 11C-4DST findings. Conclusion: The addn. of 11C-MET and 11C-4DST to 18F-FDG when performing PET/CT enabled clearer evaluations of equivocal lesions. Based on cytol. diagnostic criteria, 11C-MET and 11C-4DST were more sensitive than 18F-FDG for the detection of active lesions. 11C-MET and 11C-4DST were more useful than 18F-FDG for the detection of active lesions, esp. during the early stage of disease.
- 117Minamimoto, R.; Nakaigawa, N.; Nagashima, Y.; Toyohara, J.; Ueno, D.; Namura, K.; Nakajima, K.; Yao, M.; Kubota, K. Comparison of 11C-4DST and 18F-FDG PET/CT imaging for advanced renal cell carcinoma: Preliminary study. Abdom Radiol. 2016, 41, 521– 530, DOI: 10.1007/s00261-015-0601-y[Crossref], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fmsFelsQ%253D%253D&md5=8f36459bb884ffd39e6d6fada28cf56aComparison of 11C-4DST and 18F-FDG PET/CT imaging for advanced renal cell carcinoma: preliminary studyMinamimoto Ryogo; Nakajima Kazuhiko; Kubota Kazuo; Nakaigawa Noboru; Ueno Daiki; Namura Kazuhiro; Yao Masahiro; Nagashima Yoji; Toyohara JunAbdominal radiology (New York) (2016), 41 (3), 521-30 ISSN:.PURPOSE: 4'-[Methyl-(11)C]-thiothymidine (4DST) has been developed as an in vivo cell proliferation marker based on its DNA incorporation mechanism. This study evaluated the potential of 4DST PET/CT for imaging cellular proliferation in advanced clear cell renal cell carcinoma (RCC), compared with FDG PET/CT. Both 4DST and FDG uptake were compared with biological findings based on surgical pathology. METHODS: Five patients (3 men and 2 women; mean (±SD) age 64.8 ± 11.0 years) with a single RCC (mean diameter: 9.3 ± 3.2 cm) were examined by PET/CT using 4DST and FDG. The dynamic emission scan of 4DST for RCC over 35 min followed by a static emission scan of the body for 4DST and FDG. Then we compared the maximum standardized uptake value (SUVmax) of 20 areas of RCC on both 4DST and FDG images with (1) the Ki-67 index of cellular proliferation (2) Fuhrman grade system for nuclear grade (G) in RCC and (3) pathological phosphorylated grade of mammalian target of rapamycin (pmTOR). RESULTS: All patient cases showed clear uptake of FDG and 4DST in RCC tumors, with mean 4DST SUVmax of 7.3 ± 2.2 (range 4.3-9.4) and mean FDG SUVmax of 6.0 ± 2.8 (range 3.4-10.4). The correlation coefficient between SUVmax and Ki-67 index was higher with 4DST (r = 0.61) than with FDG (r = 0.43). Tumor 4DST uptake (G0: 1.4, G2: 2.6, G2 5.6, G4: 5.7) and tumor FDG uptake (G0: 1.8, G2: 2.9, G2 3.7, G4: 4.1) were both related to Fuhrman grade system. The 4DST uptake increased as the pmTOR grade increases (G0: 3.1, G1: 4.8, G2: 4.7, G3: 6.2); in contrast FDG uptake was unrelated to pmTOR grade (G0: 2.8, G2: 4.0, G2 3.3, G4: 3.6). CONCLUSION: A higher correlation with the proliferation of RCC was observed for 4DST than for FDG. The 4DST uptake exhibits the possibility to predict pmTOR grade, indicating that 4DST has potential for the evaluation of therapeutic effect with mTOR inhibitor in patients with RCC.
- 118Souba, W. W.; Pacitti, A. J. Review: How amino acids get into cells: Mechanisms, models, menus, and mediators. JPEN, J. Parenter. Enteral Nutr. 1992, 16, 569– 578, DOI: 10.1177/0148607192016006569[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s7ls1Wmsg%253D%253D&md5=e90b4558405af13eb46d5c37bd99eac0How amino acids get into cells: mechanisms, models, menus, and mediatorsSouba W W; Pacitti A JJPEN. Journal of parenteral and enteral nutrition (1992), 16 (6), 569-78 ISSN:0148-6071.The bloodstream provides a readily available pool of amino acids, which can be taken up by all cells of the body to support the myriad of biochemical reactions that are essential for life. The transport of amino acids into the cytoplasm occurs via functionally and biochemically distinct amino acid transport systems that have been defined on the basis of their amino acid selectivities and physico-chemical properties. Each system presumably relates to a discrete putative membrane-bound transporter protein that resides within the cell membrane and functions to translocate the amino acid from the extracellular environment into the cytoplasm. Many of these transporters require sodium for maximal activity. The sodium-dependent model presented is consistent with "preferred random" kinetics, with sodium binding preferentially before the amino acid. The transporter acts as an enzyme that catalyzes the movement of its bound amino acid (and sodium) into the cell. In this review, the authors provide a conceptual view of the mechanism of carrier-mediated amino acid transport as well as an overview of the various models that can be used in the laboratory to study this process. In addition, the known agencies that accomplish transport and their regulation by nutrition, hormones, and other mediators of critical illness are discussed.
- 119Ganapathy, V.; Thangaraju, M.; Prasad, P. D. Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond. Pharmacol. Ther. 2009, 121, 29– 40, DOI: 10.1016/j.pharmthera.2008.09.005[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFagtrrP&md5=1bebe879f37a4a55c67424394ec65a56Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyondGanapathy, Vadivel; Thangaraju, Muthusamy; Prasad, Puttur D.Pharmacology & Therapeutics (2009), 121 (1), 29-40CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review. Tumor cells have an increased demand for nutrients; this demand is met by increased availability of nutrients through vasculogenesis and by enhanced cellular entry of nutrients through upregulation of specific transporters. This review focuses on three groups of nutrient transporters relevant to cancer: glucose transporters, lactate transporters, and amino acid transporters. Tumor cells enhance glucose uptake via induction of GLUT1 and SGLT1, and coordinate the increased entry of glucose with increased glycolysis. Since enhanced glycolysis in cancer is assocd. with lactate prodn., tumor cells must find a way to eliminate lactic acid to prevent cellular acidification. This is achieved by the upregulation of MCT4, a H+-coupled lactate transporter. In addn., the Na+-coupled lactate transporter SMCT1 is silenced in cancer. SMCT1 also transports butyrate and pyruvate, which are inhibitors of histone deacetylases. The silencing of SMCT1 occurs in cancers of a variety of tissues. Re-expression of SMCT1 in cancer cell lines leads to growth arrest and apoptosis in the presence of butyrate or pyruvate, suggesting that the transporter may function as a tumor suppressor. Tumor cells meet their amino acid demands by inducing xCT/4F2hc, LAT1/4F2hc, ASCT2, and ATB0,+. xCT/4F2hc is related primarily to glutathione status, protection against oxidative stress, and cell cycle progression, whereas the other three transporters are related to amino acid nutrition. Pharmacol. blockade of LAT1/4F2hc, xCT/4F2hc, or ATB0,+ leads to inhibition of cancer cell growth. Since tumor cells selectively regulate these nutrient transporters to support their rapid growth, these transporters have potential as drug targets for cancer therapy.
- 120Langen, K.-J.; Bröer, S. Molecular transport mechanisms of radiolabeled amino acids for PET and SPECT. J. Nucl. Med. 2004, 45, 1435– 1436[PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXosVWis78%253D&md5=c1883ec8d5b26b4e3f6507063a3c9a76Molecular transport mechanisms of radiolabeled amino acids for PET and SPECTLangen, Karl JosefJournal of Nuclear Medicine (2004), 45 (9), 1435-1436CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A polemic in response to Lahoutte et al., J Nucl Med 2004;45:1591-1596. The research of Lahoutte et al. (2004) entitled "SPECT and PET amino acid tracer influx via system L (h4F2hc-hLAT1) and its transstimulation" is reviewed with commentary and refs. Lahoutte et al. analyzed the transport mechanisms of 123I-2-iodotyrosine (2IT) and compared with those of 3-123I-iodo-α-methyl-L-tyrosine (IMT) and two fluorinated amino acids currently under consideration for PET: O-(2-18F-fluoroethyl)-L-tyrosine (FET) and 2-18F-fluoro-L-tyrosine (2FT). Expression of 4F2hc-LAT1 in Xenopus laevis oocytes shows the affinity of 2IT for LAT1 is similar to that of L-tyrosine. Transtimulation expts. have shown that the influx rate of 2IT via LAT1 is comparable to that of IMT but lower than that of 2FT. In contrast, FET influx via LAT1 as found to be poor. These expts. give interesting new insights into the variable transport characteristics of these new radiolabeled amino acids. It appears that the diagnostic potential of radiolabeled amino acids will be amplified by enlarging knowledge of the mol. mechanisms involved in the transport processes.
- 121McConathy, J.; Martarello, L.; Malveaux, E. J.; Camp, V. M.; Simpson, N. E.; Simpson, C. P.; Bowers, G. D.; Olson, J. J.; Goodman, M. M. Radiolabeled amino acids for tumor imaging with PET: Radiosynthesis and biological evaluation of 2-amino-3-[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid. J. Med. Chem. 2002, 45, 2240– 2249, DOI: 10.1021/jm010241x[ACS Full Text], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFags7Y%253D&md5=24ec44499663fdb1b8938733d89c0271Radiolabeled Amino Acids for Tumor Imaging with PET: Radiosynthesis and Biological Evaluation of 2-Amino-3-[18F]fluoro-2-methylpropanoic Acid and 3-[18F]Fluoro-2-methyl-2-(methylamino)propanoic AcidMcConathy, Jonathan; Martarello, Laurent; Malveaux, Eugene J.; Camp, Vernon M.; Simpson, Nicholas E.; Simpson, Chiab P.; Bowers, Geoffrey D.; Olson, Jeffrey J.; Goodman, Mark M.Journal of Medicinal Chemistry (2002), 45 (11), 2240-2249CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Novel radiopharmaceuticals, including amino acids, that target neoplasms through their altered metabolic states have shown promising results in preclin. and clin. studies. Two fluorinated analogs of α-aminoisobutyric acid, 2-amino-3-fluoro-2-methylpropanoic acid (FAMP) and 3-fluoro-2-methyl-2-(methylamino)propanoic acid (N-MeFAMP), have been radiolabeled with fluorine-18, characterized in amino acid uptake assays, and evaluated in vivo in normal rats and a rodent tumor model. The key steps in the syntheses of both radiotracers involved the prepn. of cyclic sulfamidate precursors. Radiosyntheses of both [18F]FAMP and [18F]N-MeFAMP via no-carrier-added nucleophilic substitution provided high yields (>78% decay-cor.) in high radiochem. purity (>99%). Amino acid transport assays using 9L gliosarcoma cells demonstrated that both compds. are substrates for the A type amino acid transport system, with [18F]N-MeFAMP showing higher specificity than [18F]FAMP for A type transport. Tissue distribution studies in normal Fischer rats and Fischer rats implanted intracranially with 9L gliosarcoma tumor cells were also performed. At 60 min postinjection, the tumor vs normal brain ratio of radioactivity was 36:1 in animals receiving [18F]FAMP and 104:1 in animals receiving [18F]N-MeFAMP. On the basis of these studies, both [18F]FAMP and [18F]N-MeFAMP are promising imaging agents for the detection of intracranial neoplasms via positron emission tomog.
- 122Baek, S.; Choi, C.-M.; Ahn, S. H.; Lee, J. W.; Gong, G.; Ryu, J.-S.; Oh, S. J.; Bacher-Stier, C.; Fels, L.; Koglin, N.; Hultsch, C.; Schatz, C. A.; Dinkelborg, L. M.; Mittra, E. S.; Gambhir, S. S.; Moon, D. H. Exploratory clinical trial of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate for imaging XC- transporter using positron emission tomography in patients with non-small cell lung or breast cancer. Clin. Cancer Res. 2012, 18, 5427– 5437, DOI: 10.1158/1078-0432.CCR-12-0214[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFSgurzK&md5=eb670c06360d47d2378abdb7c008fa80Exploratory Clinical Trial of (4S)-4-(3-[18F]fluoropropyl)-l-glutamate for Imaging xC- Transporter Using Positron Emission Tomography in Patients with Non-Small Cell Lung or Breast CancerBaek, Sora; Choi, Chang-Min; Ahn, Sei Hyun; Lee, Jong Won; Gong, Gyungyub; Ryu, Jin-Sook; Oh, Seung Jun; Bacher-Stier, Claudia; Fels, Lueder; Koglin, Norman; Hultsch, Christina; Schatz, Christoph A.; Dinkelborg, Ludger M.; Mittra, Erik S.; Gambhir, Sanjiv S.; Moon, Dae HyukClinical Cancer Research (2012), 18 (19), 5427-5437CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (BAY 94-9392, alias [18F]FSPG) is a new tracer to image xC- transporter activity with positron emission tomog. (PET). We aimed to explore the tumor detection rate of [18F]FSPG in patients relative to 2-[18F]fluoro-2-deoxyglucose ([18F]FDG). The correlation of [18F]FSPG uptake with immunohistochem. expression of xC- transporter and CD44, which stabilizes the xCT subunit of system xC-, was also analyzed. Exptl. Design: Patients with non-small cell lung cancer (NSCLC, n = 10) or breast cancer (n = 5) who had a pos. [18F]FDG uptake were included in this exploratory study. PET images were acquired following injection of approx. 300 MBq [18F]FSPG. Immunohistochem. was done using xCT- and CD44-specific antibody. Results: [18F]FSPG PET showed high uptake in the kidney and pancreas with rapid blood clearance. [18F]FSPG identified all 10 NSCLC and three of the five breast cancer lesions that were confirmed by pathol. [18F]FSPG detected 59 of 67 (88%) [18F]FDG lesions in NSCLC, and 30 of 73 (41%) in breast cancer. Seven lesions were addnl. detected only on [18F]FSPG in NSCLC. The tumor-to-blood pool standardized uptake value (SUV) ratio was not significantly different from that of [18F]FDG in NSCLC; however, in breast cancer, it was significantly lower (P < 0.05). The max. SUV of [18F]FSPG correlated significantly with the intensity of immunohistochem. staining of xC- transporter and CD44 (P < 0.01). Conclusions: [18F]FSPG seems to be a promising tracer with a relatively high cancer detection rate in patients with NSCLC. [18F]FSPG PET may assess xC- transporter activity in patients with cancer. Clin Cancer Res; 18(19); 5427-37. ©2012 AACR.
- 123Huang, C.; McConathy, J. Fluorine-18 labeled amino acids for oncologic imaging with positron emission tomography. Curr. Top. Med. Chem. 2013, 13, 871– 891, DOI: 10.2174/1568026611313080002[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpslKhtL8%253D&md5=e860a056db4a4ce8278fd4fcf7cb6efaFluorine-18 labeled amino acids for oncologic imaging with positron emission tomographyHuang, Chaofeng; McConathy, JonathanCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2013), 13 (8), 871-891CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. 18F-labeled amino acids are an important class of imaging agents for positron emission tomog. (PET) that target the increased rates of amino acid transport by many tumor cells. This class of tracers is structurally diverse, and the biol. and imaging properties of a given 18F-labeled amino acid depends largely upon its mechanism of transport. The system L amino acid transport system has been a major focus of tracer development in this field, but more recently 18F-labeled amino acids have been developed for other transporters including system A, glutamine, glutamate and cationic amino acid transport systems. Radiolabeled amino acids are best established for brain tumor imaging, but there are emerging applications in other types of cancer such as neuroendocrine tumors and prostate cancer. This review provides an overview of 18F-labeled amino acids for oncol. imaging in terms of design considerations, radiosynthetic methods, and key clin. applications.
- 124del Amo, E. M.; Urtti, A.; Yliperttula, M. Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2. Eur. J. Pharm. Sci. 2008, 35, 161– 174, DOI: 10.1016/j.ejps.2008.06.015[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVyltrzP&md5=31f6073e1bc3ff74b78773373ba6a9e9Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2del Amo, Eva M.; Urtti, Arto; Yliperttula, MarjoEuropean Journal of Pharmaceutical Sciences (2008), 35 (3), 161-174CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)A review. LAT1 and LAT2 are heterodimeric large amino acid transporters that are expressed in various tissues, including the intestinal wall, blood-brain barrier, and kidney. These transporters consist of membrane spanning light chain and heavy chain, and they act as 1:1 exchangers in concert with other amino acid transporters. Only a few drugs (less than 10) are substrates of LAT1 and LAT2, including -DOPA, alpha-methyldopa, melphalan, and gabapentin. The mechanisms and substrates have been mostly elucidated using mammalian cells and Xenopus oocytes. The in vivo relevance of LAT1 and LAT2 in pharmacokinetics is obscure, because contradictory findings have been reported. It is difficult to make quant. pharmacokinetic conclusions about LAT1 and LAT2. This is due to the possible involvement of other transporters (including cross-linked heterodimers of light chain with different heavy chains, other overlapping transporters, for example TAT1), competing endogenous amino acids, and satn. phenomena. This review presents the current functional knowledge on LAT1 and LAT2 with emphasis on their potential involvement in pharmacokinetics.
- 125Castagna, M.; Shayakul, C.; Trotti, D.; Sacchi, V. F.; Harvey, W. R.; Hediger, M. A. Molecular characteristics of mammalian and insect amino acid transporters: Implications for amino acid homeostasis. J. Exp. Biol. 1997, 200, 269– 286[PubMed], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhslOnsLg%253D&md5=9590e8f83b9875d858bc0cc4c1064e47Molecular characteristics of mammalian and insect amino acid transporters: implications for amino acid homeostasisCastagna, Michela; Shayakul, Chairat; Trotti, Davide; Sacchi, V. Franca; Harvey, William R.; Hediger, Matthias A.Journal of Experimental Biology (1997), 200 (2), 269-286CODEN: JEBIAM; ISSN:0022-0949. (Company of Biologists)A review, with 51 refs. In mammalian cells, the uptake of amino acids is mediated by specialized, energy-dependent and passive transporters with overlapping substrate specificities. Most energy-dependent transporters are coupled either to the cotransport of Na+ or Cl- or to the countertransport of K+. Passive transporters are either facilitated transporters or channels. As a prelude to the mol. characterization of the different classes of transporters, we have isolated transporter cDNAs by expression-cloning with Xenopus laevis oocytes and we have characterized the cloned transporters functionally by uptake studies into oocytes using radiolabeled substrates and by electrophysiol. to det. substrate-evoked currents. Mammalian transporters investigated include the dibasic and neutral amino acid transport protein D2/NBAT (system b0+) and the Na+- and K+-dependent neuronal and epithelial high-affinity glutamate transporter EAAC1 (system X-AG). A detailed characterization of these proteins has provided new information on transport characteristics and mechanisms for coupling to different inorg. ions. This work has furthermore advanced our understanding of the roles these transporters play in amino acid homeostasis and in various pathologies. For example, in the central nervous system, glutamate transporters are critically important in maintaining the extracellular glutamate concn. below neurotoxic levels, and defects of the human D2 gene have been shown to account for the formation of kidney stones in patients with cystinuria. Using similar approaches, we are investigating the mol. characteristics of K+-coupled amino acid transporters in the larval lepidopteran insect midgut. In the larval midgut, K+ is actively secreted into the lumen through the concerted action of an apical H+ V-ATPase and an apical K+/2H+ antiporter, thereby providing the driving force for absorption of amino acids. In vivo, the uptake occurs at extremely high pH (pH 10) and is driven by a large p.d. (approx. -200mV). Studies with brush-border membrane vesicles have shown that there are several transport systems in the larval intestine with distinct amino acid and cation specificities. In addn. to K+, Na+ can also be coupled to amino acid uptake at lower pH, but the Na+/K+ ratio of the hemolymph is so low that K+ is probably the major coupling ion in vivo. The neutral amino acid transport system of larval midgut has been studied most extensively. Apart from its cation selectivity, it appears to be related to the amino acid transport system B previously characterized in vertebrate epithelial cells. Both systems have a broad substrate range which excludes 2-(methylamino)-isobutyric acid, an amino acid analog accepted by the mammalian Na+-coupled system A. To gain insights into the K+-coupling mechanism and into amino acid and K+ homeostasis in insects, current studies are designed to delineate the mol. characteristics of these insect transporters. Recent data showed that injection of mRNA prepd. from the midgut of Manduca sexta into Xenopus laevis oocytes induced a 1.5- to 2.5-fold stimulation of the Na+-dependent uptake of both leucine and phenylalanine (0.2 mmoll-1, pH8). The mol. cloning of these transporters is now in progress. Knowledge of their unique mol. properties could be exploited in the future to control disease vectors and insect pests.
- 126Yanagida, O.; Kanai, Y.; Chairoungdua, A.; Kim, D. K.; Segawa, H.; Nii, T.; Cha, S. H.; Matsuo, H.; Fukushima, J.; Fukasawa, Y.; Tani, Y.; Taketani, Y.; Uchino, H.; Kim, J. Y.; Inatomi, J.; Okayasu, I.; Miyamoto, K.; Takeda, E.; Goya, T.; Endou, H. Human L-type amino acid transporter 1 (LAT1): Characterization of function and expression in tumor cell lines. Biochim. Biophys. Acta, Biomembr. 2001, 1514, 291– 302, DOI: 10.1016/S0005-2736(01)00384-4[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXms1Olsb4%253D&md5=4a4e415390d20b4d1194cc04c103f04eHuman L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell linesYanagida, O.; Kanai, Y.; Chairoungdua, A.; Kim, D. K.; Segawa, H.; Nii, T.; Cha, S. H.; Matsuo, H.; Fukushima, J.-i.; Fukasawa, Y.; Tani, Y.; Taketani, Y.; Uchino, H.; Kim, J. Y.; Inatomi, J.; Okayasu, I.; Miyamoto, K.-i.; Takeda, E.; Goya, T.; Endou, H.Biochimica et Biophysica Acta, Biomembranes (2001), 1514 (2), 291-302CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)System L is a major nutrient transport system responsible for the transport of large neutral amino acids including several essential amino acids. We previously identified a transporter (L-type amino acid transporter 1: LAT1) subserving system L in C6 rat glioma cells and demonstrated that LAT1 requires 4F2 heavy chain (4F2hc) for its functional expression. Since its oncofetal expression was suggested in the rat liver, it has been proposed that LAT1 plays a crit. role in cell growth and proliferation. In the present study, we have examd. the function of human LAT1 (hLAT1) and its expression in human tissues and tumor cell lines. When expressed in Xenopus oocytes with human 4F2hc (h4F2hc), hLAT1 transports large neutral amino acids with high affinity (Km=∼15-∼50 μM) and L-glutamine and L-asparagine with low affinity (Km=∼1.5-∼2 mM). HLAT1 also transports D-amino acids such as D-leucine and D-phenylalanine. In addn., we show that hLAT1 accepts an amino acid-related anti-cancer agent melphalan. When loaded intracellularly, L-leucine and L-glutamine but not L-alanine are effluxed by extracellular substrates, confirming that hLAT1 mediates an amino acid exchange. HLAT1 mRNA is highly expressed in the human fetal liver, bone marrow, placenta, testis and brain. We have found that, while all the tumor cell lines examd. express hLAT1 messages, the expression of h4F2hc is varied particularly in leukemia cell lines. In Western blot anal., hLAT1 and h4F2hc have been confirmed to be linked to each other via a disulfide bond in T24 human bladder carcinoma cells. Finally, in in vitro translation, we show that hLAT1 is not a glycosylated protein even though an N-glycosylation site has been predicted in its extracellular loop, consistent with the property of the classical 4F2 light chain. The properties of the hLAT1/h4F2hc complex would support the roles of this transporter in providing cells with essential amino acids for cell growth and cellular responses, and in distributing amino acid-related compds.
- 127Okubo, S.; Zhen, H.-N.; Kawai, N.; Nishiyama, Y.; Haba, R.; Tamiya, T. Correlation of L-methyl-11C-methionine (MET) uptake with l-type amino acid transporter 1 in human gliomas. J. Neuro-Oncol. 2010, 99, 217– 225, DOI: 10.1007/s11060-010-0117-9[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGmtLbO&md5=419b9c620533421ad74e7bac4ea118ccCorrelation of l-methyl-11C-methionine (MET) uptake with l-type amino acid transporter 1 in human gliomasOkubo, Shuichi; Zhen, Hai-Ning; Kawai, Nobuyuki; Nishiyama, Yoshihiro; Haba, Reiji; Tamiya, TakashiJournal of Neuro-Oncology (2010), 99 (2), 217-225CODEN: JNODD2; ISSN:0167-594X. (Springer)L-Type amino acid transporter 1 (LAT1) is a neutral amino acid transport system and is a major route for the transport of large neutral amino acids, including methionine, through the plasma membrane. LAT1 requires the heavy chain of 4F2 cell surface antigen (4F2hc) for its functional expression. Positron emission tomog. (PET) with l-[methyl-11C] methionine (MET) provides information about amino acid metab. in brain tumors. We conducted a clinicopathol. study to elucidate the correlation of LAT1 and 4F2hc expression with MET uptake in patients with newly diagnosed human gliomas. Thirty-three newly diagnosed glioma patients were enrolled in this study. Uptake of MET in the tumor was evaluated with the max. standardized uptake value (SUVmax). Expression of the LAT1, 4F2hc, and CD34, and Ki-67 labeling index of the tumor were analyzed by immunohistochem. staining, and the correlation with the SUVmax in the tumors was examd. Expression of LAT1 and 4F2hc was higher in high-grade gliomas than in low-grade gliomas. The grade of LAT1 immunostaining increased with glioma grade. LAT1 was mainly expressed in the tumor cytoplasm and vascular endothelium and 4F2hc was mainly expressed in the tumor cytoplasm and plasma membrane. Expression of LAT1 but not 4F2hc was significantly correlated with MET SUVmax. Expression of LAT1 in the tumor vascular endothelium is significantly correlated with CD34 pos. microvessel d. In conclusion, MET SUVmax correlates with LAT1 expression in the tumor in newly diagnosed gliomas. MET transport may be increased by an increased no. of microvessels combined with a higher d. or activity of LAT1 in the tumor endothelial cells in high-grade gliomas. Use of MET-PET as a mol. target combined with anti-angiogenesis in glioma therapy should be addressed in future studies.
- 128Youland, R. S.; Kitange, G. J.; Peterson, T. E.; Pafundi, D. H.; Ramiscal, J. A.; Pokorny, J. L.; Giannini, C.; Laack, N. N.; Parney, I. F.; Lowe, V. J.; Brinkmann, D. H.; Sarkaria, J. N. The role of LAT1 in 18F-DOPA uptake in malignant gliomas. J. Neuro-Oncol. 2013, 111, 11– 18, DOI: 10.1007/s11060-012-0986-1[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFSgtLjP&md5=1dba5787353adb01070974b0876ac9f9The role of LAT1 in 18F-DOPA uptake in malignant gliomasYouland, Ryan S.; Kitange, Gaspar J.; Peterson, Timothy E.; Pafundi, Deanna H.; Ramiscal, Judi A.; Pokorny, Jenny L.; Giannini, Caterina; Laack, Nadia N.; Parney, Ian F.; Lowe, Val J.; Brinkmann, Debra H.; Sarkaria, Jann N.Journal of Neuro-Oncology (2013), 111 (1), 11-18CODEN: JNODD2; ISSN:0167-594X. (Springer)Positron emission tomog. (PET) imaging with the amino acid tracer 6-18F-fluoro-l-3,4-dihydroxy-phenylalanine (18F-DOPA) may provide better spatial and functional information in human gliomas than CT or MRI alone. The l-type amino acid transporter 1 (LAT1) is responsible for membrane transport of large neutral amino acids in normal cells. This study assessed the relationship between LAT1 expression and 18F-DOPA uptake in human astrocytomas. Endogenous LAT1 expression was measured in established glioblastoma (GBM) cell lines and primary GBM xenografts using Western blotting and quant. reverse transcription polymerase chain reaction (qRT-PCR). Uptake of 18F-DOPA was approximated in vitro using 3H-l-DOPA as an analog. Uptake of 3H-l-DOPA was assessed in cells expressing LAT1 shRNA or LAT1 siRNA and compared to non-targeted (NT) control shRNA or siRNA sequences, resp. To demonstrate the clin. relevance of these findings, LAT1 immunofluorescence staining was compared with corresponding regions of 18F-DOPA PET uptake in patients with newly diagnosed astrocytomas. LAT1 mRNA and protein expression varies in GBM, and the extent of 3H-l-DOPA uptake was pos. correlated with endogenous LAT1 expression. Stable shRNA-mediated LAT1 knockdown in T98 and GBM28 reduced 3H-l-DOPA uptake relative to NT shRNA by 57 (P < 0.0001) and 52 % (P < 0.001), resp. Transient siRNA-mediated LAT1 knockdown in T98 reduced 3H-l-DOPA uptake relative to NT siRNA up to 68 % (P < 0.01). In clin. samples, LAT1 expression pos. correlated with 18F-DOPA PET uptake (P = 0.04). Expression of LAT1 is strongly assocd. with 3H-l-DOPA uptake in vitro and 18F-DOPA uptake in patient biopsy samples. These results define LAT1 as a key determinant of 18F-DOPA accumulation in GBM.
- 129Papin-Michault, C.; Bonnetaud, C.; Dufour, M.; Almairac, F.; Coutts, M.; Patouraux, S.; Virolle, T.; Darcourt, J.; Burel-Vandenbos, F. Study of LAT1 expression in brain metastases: Towards a better understanding of the results of positron emission tomography using amino acid tracers. PLoS One 2016, 11, e0157139 DOI: 10.1371/journal.pone.0157139[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslOnsL%252FO&md5=78ac27b61eabe4216a6b0a1eed0a74c3Study of LAT1 expression in brain metastases: towards a better understanding of the results of positron emission tomography using amino acid tracersPapin-Michault, Caroline; Bonnetaud, Christelle; Dufour, Maxime; Almairac, Fabien; Coutts, Mickael; Patouraux, Stephanie; Virolle, Thierry; Darcourt, Jacques; Burel-Vandenbos, FannyPLoS One (2016), 11 (6), e0157139/1-e0157139/12CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Positron emission tomog. using radiolabeled amino acid (PET-AA) appears to be promising in distinguishing between recurrent tumor and radionecrosis in the follow-up of brain metastasis (BM). The amino acid transporter LAT1 and its cofactor CD98, which are involved in AA uptake, have never been investigated in BM. The aim of our study was to det. and compare the expression of LAT1 and CD98 in BM and in non-tumoral brain tissue (NT). The expression of LAT1 and CD98 were studied by immunohistochem. in 67 BM, including 18 BM recurrences after radiotherapy, in 53 NT, and in 13 cases of patients with previously irradiated brain tumor and investigated by [18F] FDOPA-PET. LAT1 and CD98 expression were detected in 98.5%and 59.7%of BM resp. and were significantly assocd. with BM tissue as compared to NT (p<0.001). LAT1 expression in recurrent BM was significantly increased as compared to newly occurring BM. Ten cases investigated by [18F] FDOPA-PET corresponding to recurrent BM displayed significant [18F] FDOPA uptake and LAT1 overexpression whereas three cases corresponding to radionecrosis showed no or low uptake and LAT1 expression. LAT1 expression level and [18F] FDOPA uptake were significantly correlated. In conclusion, we hypothesized that BM may overexpress the AA transporter LAT1.We have shown that LAT1 overexpression was common in BM and was specific for BM as compared to healthy brain. These results could explain the specific BM uptake on PET-AA.
- 130Verrey, F. System L: Heteromeric exchangers of large, neutral amino acids involved in directional transport. Pfluegers Arch. 2003, 445, 529– 533, DOI: 10.1007/s00424-002-0973-z[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjt1Ggu7w%253D&md5=cb3de53aafde4ca0d2a6750f784ff827System L: Heteromeric exchangers of large, neutral amino acids involved in directional transportVerrey, FrancoisPfluegers Archiv (2003), 445 (5), 529-533CODEN: PFLABK; ISSN:0031-6768. (Springer-Verlag)A review. The plasma membrane transport system L is in many cells the only (efficient) pathway for the import of large branched and arom. neutral amino acids. The corresponding transporters are hetero(di)mers composed of a catalytic subunit, LAT1 or LAT2 (light chain glycoprotein-assocd. amino acid transporter), assocd. covalently with the glycoprotein 4F2hc/CD98 (heavy chain). The tissue distribution of LAT1 suggests that it is involved mainly in transporting amino acids into growing cells and across some endothelial/epithelial secretory barriers, whereas the localization of LAT2 indicates that it is mainly involved in the basolateral efflux step of transepithelial (re)absorptive amino acid transport. However, system L transporters are obligatory amino acid exchangers with 1:1 stoichiometry, with similar (but not identical) intra- and extracellular substrate selectivities and with highly asym. apparent affinities (low affinity inside). Therefore, net directional transport of large, neutral amino acids by system L depends on the parallel expression of a unidirectional transporter with overlapping selectivity (for instance systems A or N) that provides/recycles amino acids that drive system L exchange function. By mediating the regulated flux of these exchange substrates, unidirectional transporters control the activity of system L.
- 131Makrides, V.; Bauer, R.; Weber, W.; Wester, H.-J.; Fischer, S.; Hinz, R.; Huggel, K.; Opfermann, T.; Herzau, M.; Ganapathy, V.; Verrey, F.; Brust, P. Preferred transport of O-(2-[18F]fluoroethyl)-D-tyrosine (D-FET) into the porcine brain. Brain Res. 2007, 1147, 25– 33, DOI: 10.1016/j.brainres.2007.02.008[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksVOqtL8%253D&md5=cf68e120baf941dc0aef1399d99f8108Preferred transport of O-(2-[18F]fluoroethyl)-D-tyrosine (D-FET) into the porcine brainMakrides, Victoria; Bauer, Reinhard; Weber, Wolfgang; Wester, Hans-Juergen; Fischer, Steffen; Hinz, Rainer; Huggel, Katja; Opfermann, Thomas; Herzau, Michael; Ganapathy, Vadivel; Verrey, Francois; Brust, PeterBrain Research (2007), 1147 (), 25-33CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)Amino acids are valuable tracers for brain tumor imaging with positron emission tomog. (PET). In this study the transport of O-(2-[18F]fluoroethyl)-D-tyrosine (D-FET) across the blood-brain barrier (BBB) was studied with PET in anesthetized piglets and patients after subtotal resection of brain tumors and compared with O-(2-[18F]fluoroethyl)-L-tyrosine (L-FET) and 3-O-methyl-6-[18F]fluoro-D-DOPA (L-OMFD). In piglets, compartmental modeling of PET data was used to calc. the rate consts. for the blood-brain (K1) and the brain-blood (k2) transfer of D-FET, L-FET and L-OMFD. In patients standardized uptake values (SUVs) were calcd. in brain cortex and lesions. Addnl., affinity detns. on various amino acid transporters (LAT1, LAT2, PAT1, XPCT) were performed in vitro using unlabeled D-FET, L-FET and L-OMFD. The initial brain uptake of D-FET in piglets was more than two-fold higher than that of L-FET, whereas the initial brain uptake of D-FET in patients was similar to that of L-FET. Calcn. of K1 and k2 from the brain uptake curves and the plasma input data in piglets revealed about 4- and 2-fold higher values for D-FET compared to L-FET and L-OMFD, resp. The distribution vol. of D-FET in the piglet brain was slightly higher than that of L-FET as it was also found for most other organs. In brain tumor patients, initial D-FET uptake in the brain was similar to that of L-FET but showed faster tracer washout. L-FET uptake remained rather const. and provided a better delineation of residual tumor than D-FET. In conclusion, our data indicate considerable differences of stereoselective amino acid transport at the BBB in different species. Therefore, the results from animal expts. concerning BBB amino acid transport may not be transferable to humans.
- 132Sun, A.; Liu, X.; Tang, G. Carbon-11 and fluorine-18 labeled amino acid tracers for positron emission tomography imaging of tumors. Front. Chem. 2018, 5, 124, DOI: 10.3389/fchem.2017.00124
- 133Baldessarini, R. J.; Kopin, I. J. S-adenosylmethionine in brain and other tissues. J. Neurochem. 1966, 13, 769– 777, DOI: 10.1111/j.1471-4159.1966.tb09884.x[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28Xks1Oksr0%253D&md5=2e796ae995785216b877230fe3fd81e7S-Adenosylmethionine in brain and other tissuesBaldessarini, Ross J.; Kopin, Irwin J.Journal of Neurochemistry (1966), 13 (8), 769-77CODEN: JONRA9; ISSN:0022-3042.A sensitive and specific isotope diln. method was described for assay of an active Me donor, S-adenosylmethionine (I). Most of the mammalian tissues, including brain, showed measurable amts. of I with the highest levels noted in liver, adrenal, and pineal tissues. The level of I in brain and liver, detd. during various developmental stages of the rats, showed max. activity in the newborn which gradually fell reaching a steady state in the adult animal. The rate of turnover and the level of I in brain was lower than in liver. Since I administered into blood was recovered poorly in brain, it was suggested that I seen in brain might be synthesized locally from methionine entering into the central nervous system.
- 134Veronese, M.; Schmidt, K. C.; Smith, C. B.; Bertoldo, A. Use of spectral analysis with iterative filter for voxelwise determination of regional rates of cerebral protein synthesis with L -[1-11C]leucine PET. J. Cereb. Blood Flow Metab. 2012, 32, 1073– 1085, DOI: 10.1038/jcbfm.2012.27[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvFemt7Y%253D&md5=c01ddf0757e41e95fb8b721695024ae7Use of spectral analysis with iterative filter for voxelwise determination of regional rates of cerebral protein synthesis with L-[1-11C]leucine PETVeronese, Mattia; Schmidt, Kathleen C.; Smith, Carolyn Beebe; Bertoldo, AlessandraJournal of Cerebral Blood Flow & Metabolism (2012), 32 (6), 1073-1085CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)A spectral anal. approach was used to est. kinetic parameters of the L-[1-11C]leucine positron emission tomog. (PET) method and regional rates of cerebral protein synthesis (rCPS) on a voxel-by-voxel basis. Spectral anal. applies to both heterogeneous and homogeneous tissues; it does not require prior assumptions concerning no. of tissue compartments. Parameters estd. with spectral anal. can be strongly affected by noise, but numerical filters improve estn. performance. Spectral anal. with iterative filter (SAIF) was originally developed to improve estn. of leucine kinetic parameters and rCPS in region-of-interest (ROI) data analyses. In the present study, we optimized SAIF for application at the voxel level. In measured L-[1-11C]leucine PET data, voxel-level SAIF parameter ests. averaged over all voxels within a ROI (mean voxel-SAIF) generally agreed well with corresponding ests. derived by applying the originally developed SAIF to ROI time-activity curves (ROI-SAIF). Region-of-interest-SAIF and mean voxel-SAIF ests. of rCPS were highly correlated. Simulations showed that mean voxel-SAIF rCPS ests. were less biased and less variable than ROI-SAIF ests. in the whole brain and cortex; biases were similar in white matter. We conclude that estn. of rCPS with SAIF is improved when the method is applied at voxel level than in ROI anal. Journal of Cerebral Blood Flow & Metab. (2012) 32, 1073-1085; doi:10.1038/jcbfm.2012.27; published online 7 March 2012.
- 135Ishiwata, K.; Vaalburg, W.; Elsinga, P. H.; Paans, A. M.; Woldring, M. G. Comparison of L-[1–11C]methionine and L-methyl-[11C]methionine for measuring in vivo protein synthesis rates with PET. J. Nucl. Med. 1988, 29, 1419– 1427[PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1czgtVaisw%253D%253D&md5=a5fe80f8123662c90cb212d270f17dccComparison of L-[1-11C]methionine and L-methyl-[11C]methionine for measuring in vivo protein synthesis rates with PETIshiwata K; Vaalburg W; Elsinga P H; Paans A M; Woldring M GJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1988), 29 (8), 1419-27 ISSN:0161-5505.To evaluate the feasibility of using either L-[1-11C]-methionine or L-[methyl-11C]methionine for measuring protein synthesis rates by positron emission tomography (PET) in normal and neoplastic tissues, distribution and metabolic studies with 14C- and 11C-labeled methionines were carried out in rats bearing Walker 256 carcinosarcoma. The tissue distributions of the two 14C-labeled methionines were similar except for liver tissue. Similar distribution patterns were observed in vivo by PET using 11C-labeled methionines. The highest 14C incorporation rate into the protein-bound fraction was found in the liver followed by tumor, brain, and pancreas. The incorporation rates in liver and pancreas were different for the two methionines. By chloroform-methanol fractionation of these four tissues, in liver significantly different amounts of 14C were observed in macromolecules. Also in brain tissue slight differences were found. By HPLC analyses of the protein-free fractions of plasma, tumor, and brain tissue at 60 min after injection, for both methionines several 14C-labeled metabolites in different amounts, were detected. About half of the 14C-labeled material in the protein-free fraction was found to be methionine. In these three tissues the amount of nonprotein metabolites and [14C]bicarbonate amount ranged from 10% to 17% and 12% to 15% for L-[1-14C]methionine and L-[methyl-14C]methionine, respectively. From these results it can be concluded that the minor metabolic pathways have to be investigated in order to quantitatively model the protein synthesis by PET.
- 136Lebarre, J.; Crouzel, C.; Donie, P. Preliminary results on the biosynthesis of [11C]phenylalanine using a photosynthetic bacterium. Acta Radiol. Suppl. 1991, 376, 109[PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK383hsVWmtg%253D%253D&md5=d1a825f8674412693fcf6d65f0195bddPreliminary results on the biosynthesis of [11C]phenylalanine using a photosynthetic bacteriumLebarre J; Crouzel C; Donie PActa radiologica. Supplementum (1991), 376 (), 109 ISSN:0365-5954.There is no expanded citation for this reference.
- 137de Boer, J. R.; Pruim, J.; van der Laan, B. F. A. M.; Que, T. H.; Willemsen, A. T. M.; Albers, F. W. J.; Vaalburg, W. L-1-11C-tyrosine PET in patients with laryngeal carcinomas: Comparison of standardized uptake value and protein synthesis rate. J. Nucl. Med. 2003, 44, 341– 346[PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislKntb0%253D&md5=486cda911ea8eaa525f5418177584a19L-1-11C-tyrosine PET in patients with laryngeal carcinomas: comparison of standardized uptake value and protein synthesis ratede Boer, Jurjan R.; Pruim, Jan; van der Laan, Bernard F. A. M.; Que, Tjin H.; Willemsen, Antoon T. M.; Albers, Frans W. J.; Vaalburg, WillemJournal of Nuclear Medicine (2003), 44 (3), 341-346CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)PET with L-1-11C-tyrosine (TYR) can measure and quantify increased protein synthesis in tumor tissue in vivo. For quantification of the protein synthesis rate (PSR), arterial cannulation with repeated blood sampling to obtain the plasma input function and a dynamic TYR PET study to calc. a time-activity curve are necessary. In most PET studies the standardized uptake value (SUV) method is used to quantify tumor activity. The SUV can be calcd. without repeated arterial blood sampling and prolonged scanning time, as required for detn. of the PSR. The relationship between PSR and SUV is largely unknown and different factors can cause wide variability in the SUV. Therefore, the comparison of the abs. quantification method (PSR) with the SUV method is obligatory to det. the possible use of noninvasive PET in head and neck oncol. Methods: Twenty-four patients with proven squamous cell carcinomas of the larynx (T1-T4) were studied using dynamic TYR PET. The PSRs of tumor and nontumor (background) regions were detd. Four different methods were used to calc. the SUV: uncorrected SUV (SUVBW); and SUVs cor. for body surface area (SUVBSA), for lean body mass (SUVLBM), and for the Quetelet index (SUVQI). Correlations between PSR values and SUVs were calcd. Results: The PSR of all tumors was significantly higher (P < 0.001) than the PSR of nontumor tissue. The correlations of SUVBW, SUVBSA, SUVLBM, and SUVQI with the quant. values of the PSR were high (r = 0.84-0.90). The best correlation was obsd. with the SUV based on the LBM (SUVLBM). Conclusion: High correlation between the quant. values (PSR) and the SUVs offers the possibility to use noninvasive TYR PET for detection and reliable quantification of primary head and neck tumors.
- 138Herholz, K.; Holzer, T.; Bauer, B.; Schroder, R.; Voges, J.; Ernestus, R. I.; Mendoza, G.; Weber-Luxenburger, G.; Lottgen, J.; Thiel, A.; Wienhard, K.; Heiss, W. D. 11C-methionine PET for differential diagnosis of low-grade gliomas. Neurology 1998, 50, 1316– 1322, DOI: 10.1212/WNL.50.5.1316[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1c3lsFCiuw%253D%253D&md5=94195d9cfab6935676284088ca0b2ed711C-methionine PET for differential diagnosis of low-grade gliomasHerholz K; Holzer T; Bauer B; Schroder R; Voges J; Ernestus R I; Mendoza G; Weber-Luxenburger G; Lottgen J; Thiel A; Wienhard K; Heiss W DNeurology (1998), 50 (5), 1316-22 ISSN:0028-3878.Management of low-grade gliomas continues to be a challenging task, because CT and MRI do not always differentiate from nontumoral lesions. Furthermore, tumor extent and aggressiveness often remain unclear because of a lack of contrast enhancement. Previous studies indicated that large neutral amino acid tracers accumulate in most brain tumors, including low-grade gliomas, probably because of changes of endothelial and blood-brain barrier function. We describe 11C-methionine uptake measured with PET in a series of 196 consecutive patients, most of whom were studied because of suspected low-grade gliomas. Uptake in the most active lesion area, relative to contralateral side, was significantly different among high-grade gliomas, low-grade gliomas, and chronic or subacute nontumoral lesions, and this difference was independent from contrast enhancement in CT or MRI. Corticosteroids had no significant effect on methionine uptake in low-grade gliomas but reduced uptake moderately in high-grade gliomas. Differentiation between gliomas and nontumoral lesions by a simple threshold was correct in 79%. Recurrent or residual tumors had a higher uptake than primary gliomas. In conclusion, the high sensitivity of 11C-methionine uptake for functional endothelial or blood-brain barrier changes suggests that this tracer is particularly useful for evaluation and follow-up of low-grade gliomas.
- 139Becherer, A.; Karanikas, G.; Szabo, M.; Zettinig, G.; Asenbaum, S.; Marosi, C.; Henk, C.; Wunderbaldinger, P.; Czech, T.; Wadsak, W.; Kletter, K. Brain tumour imaging with PET: A comparison between [18F]fluorodopa and [11C]methionine. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 1561– 1567, DOI: 10.1007/s00259-003-1259-1[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXosVCqtLk%253D&md5=039f1f3fc46c73281b7122386a574388Brain tumour imaging with PET: a comparison between [18F]fluorodopa and [11C]methionineBecherer, Alexander; Karanikas, Georgios; Szabo, Monica; Zettinig, Georg; Asenbaum, Susanne; Marosi, Christine; Henk, Christine; Wunderbaldinger, Patrick; Czech, Thomas; Wadsak, Wolfgang; Kletter, KurtEuropean Journal of Nuclear Medicine and Molecular Imaging (2003), 30 (11), 1561-1567CODEN: EJNMA6; ISSN:1619-7070. (Springer-Verlag)Imaging of amino acid transport in brain tumors is more sensitive than fluorine-18 2-fluoro-deoxyglucose positron emission tomog. (PET). The most frequently used tracer in this field is carbon-11 methionine (MET), which is unavailable for PET centers without a cyclotron because of its short half-life. The purpose of this study was to evaluate the performance of 3,4-dihydroxy-6-[18F]fluoro-phenylalanine (FDOPA) in this setting, in comparison with MET. Twenty patients with known supratentorial brain lesions were referred for PET scans with FDOPA and MET. The diagnoses were 18 primary brain tumors, one metastasis and one non-neoplastic cerebral lesion. All 20 patients underwent PET with FDOPA (100 MBq, 20 min p.i.), and 19 of them also had PET scans with MET (800 MBq, 20 min p.i.). In all but one patient a histol. diagnosis was available. In 15 subjects, histol. was known from previous surgical interventions; in five of these patients, as well as in four previously untreated patients, histol. was obtained after PET. In one untreated patient, confirmation of PET was possible solely by correlation with MRI; a histol. diagnosis became available 10 mo later. MET and FDOPA images matched in all patients and showed all lesions as hot spots with higher uptake than in the contralateral brain. Standardized uptake value ratios, tumor/contralateral side (mean±SD), were 2.05±0.91 for MET and 2.04±0.53 for FDOPA (NS). The benign lesion, which biopsy revealed to be a focal demyelination, was false pos., showing increased uptake of MET and FDOPA. We conclude that FDOPA is accurate as a surrogate for MET in imaging amino acid transport in malignant cerebral lesions for the purpose of visualization of vital tumor tissue. It combines the good phys. properties of 18F with the pharmacol. properties of MET and might therefore be a valuable PET radiopharmaceutical in brain tumor imaging.
- 140Långström, B.; Antoni, G.; Gullberg, P.; Halldin, C.; Malmborg, P.; Någren, K.; Rimland, A.; Svärd, H. Synthesis of L- and D-[methyl-11C]methionine. J. Nucl. Med. 1987, 28, 1037– 1040[PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s3isFWrtQ%253D%253D&md5=75dfaf0560377e6d536b87489db00a24Synthesis of L- and D-[methyl-11C]methionineLangstrom B; Antoni G; Gullberg P; Halldin C; Malmborg P; Nagren K; Rimland A; Svard HJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1987), 28 (6), 1037-40 ISSN:0161-5505.This report describes the synthesis of L- and D-[methyl-11C]methionine in pure enantiomeric forms. The compounds were prepared routinely approximately 1,000 times with less than 20 failures. Starting with carbon-11 (11C) methyl iodide, a simple one-carbon precursor produced from a one-pot or a two-pot apparatus, L- and D-[methyl-11C]methionine were prepared, respectively, with an optical purity higher than 99% in 40%-90% radiochemical yields. The total time for synthesis, starting from [11C]carbon dioxide, was 12-15 min. The crude product usually had a radiochemical purity greater than 95%. The total time for synthesis, including LC purification, was 20-30 min. The radiochemical purity of the product in each case was greater than 98%.
- 141Okochi, Y.; Nihashi, T.; Fujii, M.; Kato, K.; Okada, Y.; Ando, Y.; Maesawa, S.; Takebayashi, S.; Wakabayashi, T.; Naganawa, S. Clinical use of 11C-methionine and 18F-FDG-PET for germinoma in central nervous system. Ann. Nucl. Med. 2014, 28, 94– 102, DOI: 10.1007/s12149-013-0787-4[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVOnsL3F&md5=2909502bf46e171ce67acdf88c01035dClinical use of 11C-methionine and 18F-FDG-PET for germinoma in central nervous systemOkochi, Yoshiyuki; Nihashi, Takashi; Fujii, Masazumi; Kato, Katsuhiko; Okada, Yumiko; Ando, Yoshio; Maesawa, Satoshi; Takebayashi, Shigenori; Wakabayashi, Toshihiko; Naganawa, ShinjiAnnals of Nuclear Medicine (2014), 28 (2), 94-102CODEN: ANMEEX; ISSN:0914-7187. (Springer Japan)Objective: The purpose of this study was to examine the 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) positron emission tomog. (PET) findings of central nervous system (CNS) germinoma and the diagnostic utility of these findings. Methods: We retrospectively evaluated the cases of 10 patients who were diagnosed with CNS germinoma according to their histopathol. or clin. findings. All the patients underwent pretreatment MET and/or FDG-PET scans, and the resultant images were assessed qual. and quant. In the qual. assessments, we used 3- and 5-grade visual scoring systems for the MET- and FDG-PET images, resp. In the quant. assessments, the maximal standardized uptake value (SUVmax) and the ratio of the SUVmax of the tumor (T) divided by the mean SUV for the normal white or gray matter [T/N (WM), T/N (GM)], was calcd. Results: The mean and SD values of SUVmax, T/N (WM), and T/N (GM) were 1.9 ± 1.4, 2.5 ± 1.3, and 1.7 ± 0.9 on MET-PET and 5.8 ± 2.2, 1.6 ± 0.5, and 0.8 ± 0.2 on FDG-PET, resp. On MET-PET, only one lesion was not detected. On the other hand, on FDG-PET all of the lesions exhibited uptake values that were intermediate between those of the normal white matter and gray matter. Conclusion: In terms of its tumor-contouring ability, MET is a good tracer for diagnosing CNS germinomas; therefore, MET-PET is considered to be useful for planning biopsies or surgery. Although FDG-PET is capable of detecting CNS germinomas, it produced insufficient image contrast in the present study. Further studies are needed before FDG-PET can be used in clin. examns. of CNS germinoma.
- 142Phi, J. H.; Paeng, J. C.; Lee, H. S.; Wang, K. C.; Cho, B. K.; Lee, J. Y.; Park, S. H.; Lee, J.; Lee, D. S.; Kim, S. K. Evaluation of focal cortical dysplasia and mixed neuronal and glial tumors in pediatric epilepsy patients using 18F-FDG and 11C-methionine PET. J. Nucl. Med. 2010, 51, 728– 734, DOI: 10.2967/jnumed.109.070920[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3czgslCltQ%253D%253D&md5=c1c6a8190d71b4bfeefee76109d76d6eEvaluation of focal cortical dysplasia and mixed neuronal and glial tumors in pediatric epilepsy patients using 18F-FDG and 11C-methionine petPhi Ji Hoon; Paeng Jin Chul; Lee Hyo Sang; Wang Kyu-Chang; Cho Byung-Kyu; Lee Ji-Yeoun; Park Sung-Hye; Lee Joongyub; Lee Dong Soo; Kim Seung-KiJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2010), 51 (5), 728-34 ISSN:.UNLABELLED: Focal cortical dysplasia (FCD) and mixed neuronal and glial tumors share many clinical characteristics; therefore, the presurgical differential diagnosis of these diseases using MRI is difficult in some cases. The aim of this study was to determine whether (11)C-methionine PET, compared with (18)F-FDG PET, was useful for the evaluation of these diseases. METHODS: The clinical and imaging data of 30 pediatric lesional epilepsy patients pathologically diagnosed with FCD, dysembryoplastic neuroepithelial tumor (DNT), or ganglioglioma were reviewed. Eleven patients had FCD, 8 patients had a DNT, and 11 patients had a ganglioglioma. (18)F-FDG and (11)C-methinine PET scans were obtained from 25 patients and 15 patients, respectively. Visual grading analysis and quantitative assessment of (18)F-FDG and (11)C-methionine PET, represented as a lesion-to-gray matter ratio (LGR), were performed. RESULTS: In the visual grading analysis, both (18)F-FDG PET and (11)C-methionine PET detected a significant difference among the 3 disease groups (P = 0.033 and P = 0.016, respectively), but discrimination of FCD from mixed neuronal and glial tumors was possible only with (11)C-methionine PET. The mean LGR of (18)F-FDG PET was 0.502 +/- 0.119 for FCD, 0.631 +/- 0.107 for DNTs, and 0.620 +/- 0.196 for gangliogliomas; there was no significant difference in LGR among the groups (P = 0.111). However, the mean LGR of (11)C-methionine PET was 1.078 +/- 0.182 for FCD, 1.564 +/- 0.368 for DNT, and 2.114 +/- 0.723 for gangliogliomas; there was a significant difference in LGR among the groups (P = 0.014). Post hoc analysis revealed that the LGR of FCD was significantly different from that of DNTs and gangliogliomas. The mean LGR value of DNTs fell between those of FCD and gangliogliomas. CONCLUSION: Although (18)F-FDG plays a major role in the preoperative work-up of epilepsy surgery patients, it appears from this study that (18)F-FDG does not contribute to the differential diagnosis and that another tracer such as (11)C-methinine is required. (11)C-methinine PET results correlated well with the pathologic spectrum in pediatric lesional epilepsy patients.
- 143Arita, H.; Kinoshita, M.; Okita, Y.; Hirayama, R.; Watabe, T.; Ishohashi, K.; Kijima, N.; Kagawa, N.; Fujimoto, Y.; Kishima, H.; Shimosegawa, E.; Hatazawa, J.; Hashimoto, N.; Yoshimine, T. Clinical characteristics of meningiomas assessed by 11C-methionine and 18F-fluorodeoxyglucose positron-emission tomography. J. Neuro-Oncol. 2012, 107, 379– 386, DOI: 10.1007/s11060-011-0759-2[Crossref], [PubMed], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC383ovFantQ%253D%253D&md5=49a7f78b3de7666f24a9c63aa725a65dClinical characteristics of meningiomas assessed by 11C-methionine and 18F-fluorodeoxyglucose positron-emission tomographyArita Hideyuki; Kinoshita Manabu; Okita Yoshiko; Hirayama Ryuichi; Watabe Tadashi; Ishohashi Kayako; Kijima Noriyuki; Kagawa Naoki; Fujimoto Yasunori; Kishima Haruhiko; Shimosegawa Eku; Hatazawa Jun; Hashimoto Naoya; Yoshimine ToshikiJournal of neuro-oncology (2012), 107 (2), 379-86 ISSN:.The clinical course of meningioma varies from case to case, despite similar characteristics on magnetic resonance (MR) imaging. Functional imaging including (11)C-methionine and (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) has been widely studied for noninvasive preoperative evaluation of brain tumors. However, few reports have examined correlations between meningiomas and findings on (11)C-methionine and FDG PET. The objective of this study was to clarify the relationship between tumor characteristics and (11)C-methionine and FDG uptake in meningiomas. For 68 meningiomas in 51 cases, (11)C-methionine uptake was evaluated by measuring both mean and maximum tumor/normal (T/N) ratio for the whole area of the tumors. FDG uptake in 44 of those meningiomas was also analyzed. Tumor size was measured volumetrically, and tumor-doubling time was estimated. Histopathological evaluation was performed in 19 surgical cases. Mean and maximum T/N ratios of (11)C-methionine PET were significantly higher in skull-base lesions than in non-skull-base lesions. Correlations of mean and maximum T/N ratio of (11)C-methionine PET with tumor-doubling time, MIB-1 labeling index, microvessel density and World Health Organization grading were not significant. Mean T/N ratio of (11)C-methionine PET correlated significantly with tumor volume according to logarithm regression modeling (P < 0.0001, R = 0.544). However, mean and maximum T/N ratio of FDG-PET correlated with none of the tumor characteristics described above. These results suggest that (11)C-methionine uptake correlates with tumor volume, but not with tumor aggressiveness.
- 144Takao, H.; Momose, T.; Ohtomo, K. Methionine and glucose metabolism of central neurocytoma: A PET study. Clinical Nuclear Medicine. 2004, 29, 838– 839, DOI: 10.1097/00003072-200412000-00023[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2crnt1anug%253D%253D&md5=d4fd2edff6cf55c30e3845aad2cc5f74Methionine and glucose metabolism of central neurocytoma: a PET studyTakao Hidemasa; Momose Toshimitsu; Ohtomo KuniClinical nuclear medicine (2004), 29 (12), 838-9 ISSN:0363-9762.There is no expanded citation for this reference.
- 145Van Laere, K.; Ceyssens, S.; Van Calenbergh, F.; de Groot, T.; Menten, J.; Flamen, P.; Bormans, G.; Mortelmans, L. Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: Sensitivity, inter-observer variability and prognostic value. Eur. J. Nucl. Med. Mol. Imaging 2005, 32, 39– 51, DOI: 10.1007/s00259-004-1564-3[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cnivVymtQ%253D%253D&md5=e9a84a1fea65e6826485163d046a4a70Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: sensitivity, inter-observer variability and prognostic valueVan Laere Koen; Ceyssens Sarah; Van Calenbergh Frank; de Groot Tjibbe; Menten Johan; Flamen Patrick; Bormans Guy; Mortelmans LucEuropean journal of nuclear medicine and molecular imaging (2005), 32 (1), 39-51 ISSN:1619-7070.PURPOSE: 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) PET imaging studies allow the investigation of metabolism and amino acid transport in brain tumours. Their (relative) usefulness and prognostic value in suspected recurrence or progression of primary brain tumours after previous therapy is an issue of debate. The aim of this study was to compare directly both radioligands in this setting. METHODS: Cerebral uptake of FDG and MET was determined sequentially on the same day in 30 patients (21 males, nine females; age 40.4+/-15.6 years), on average 4.0 years (range 0.1-18) after therapy for a primary brain tumour (23 grade II-IV astrocytomas, four oligodendrogliomas and three mixed oligo-astrocytomas). Images were acquired on a Siemens HR+ dedicated PET camera. Two observers scored FDG and MET scans independently. Semi-quantitative indices defined by the tumour (maximum)-to-background ratio were calculated based on manual ROI delineation and by using MET ROIs for FDG after automated co-registration. Patient follow-up was conducted until the last contact with inconspicuous clinical findings (average 41 months, range 12-62 months after PET) [(n=10)] or until death (n=20). RESULTS: Overall median survival was 15.0 months. MET showed pathologically increased uptake in 28/30 scans, and FDG in 17/30. The inter-observer agreement was 100% for MET and 73% for FDG. Using Kaplan-Meier survival analysis, significant differences were found for both FDG (cut-off 0.8, log-rank p=0.007) and MET (cut-off 2.2, log-rank p=0.014). The combination of FDG and MET information resulted in the highest prognostic accuracy (p=0.003), while MET alone was the best prognostic predictor in the subgroup of patients with primary astrocytoma (n=23). CONCLUSION: FDG and MET PET studies provide complementary prognostic information in patients with suspected brain tumour recurrence or progression after primary therapy. MET is considered the single agent of choice in the evaluation of these patients because of its sensitivity and clearer delineation of the suspected recurrence.
- 146Galldiks, N.; Kracht, L. W.; Burghaus, L.; Thomas, A.; Jacobs, A. H.; Heiss, W.; Herholz, K. Use of 11C-methionine PET to monitor the effects of Temozolomide chemotherapy in malignant gliomas. Eur. J. Nucl. Med. Mol. Imaging 2006, 33, 516– 524, DOI: 10.1007/s00259-005-0002-5[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XktFSqsLY%253D&md5=3504479e710ed5046d5c51a461aea10fUse of 11C-methionine PET to monitor the effects of temozolomide chemotherapy in malignant gliomasGalldiks, Norbert; Kracht, Lutz W.; Burghaus, Lothar; Thomas, Anne; Jacobs, Andreas H.; Heiss, Wolf-Dieter; Herholz, KarlEuropean Journal of Nuclear Medicine and Molecular Imaging (2006), 33 (5), 516-524CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: The purpose of this study was to monitor the metabolic effects of temozolomide (TMZ) chemotherapy in malignant gliomas by means of repeated positron emission tomog. (PET) with [11C]methionine (MET). Methods: Fifteen patients with histol. proven malignant glioma were treated by TMZ chemotherapy. MET-PET studies were performed before and after the third cycle of TMZ chemotherapy in all patients, and in 12 patients also after the sixth cycle. Gadolinium-enhanced MRI studies were performed in 12 patients before the first and after the sixth cycle. Clin. status was assessed by the modified Rankin scale. Long-term outcome was assessed by calcg. the time to progression (TTP) in months. Results: Decline in MET uptake during therapy corresponded to a stable clin. status. The median TTP was significantly longer in patients with decline in MET uptake than in those with increasing MET uptake (23 vs 3.5 mo; p=0.01, log rank test). There was no significant correlation between change in MET uptake and change in contrast enhancement during treatment for all patients. Conclusion: The present data demonstrate that clin. stability, which is often achieved under TMZ chemotherapy of malignant glioma, corresponds to a decline in or stability of tumor amino acid metab. Tumor responses can already be demonstrated with MET-PET after three cycles of chemotherapy, and absence of progression at that time indicates a high probability of further stability during the next three cycles. A redn. in MET uptake during TMZ treatment predicts a favorable clin. outcome. Mol. imaging of amino acid uptake by MET-PET offers a new method of measurement of the biol. activity of recurrent glioma.
- 147Hatakeyama, T.; Kawai, N.; Nishiyama, Y.; Yamamoto, Y.; Sasakawa, Y.; Ichikawa, T.; Tamiya, T. 11C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma. Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 2009– 2017, DOI: 10.1007/s00259-008-0847-5[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1artLzK&md5=aaa0b92e8fd9738411adabe8e1c733b711C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed gliomaHatakeyama, Tetsuhiro; Kawai, Nobuyuki; Nishiyama, Yoshihiro; Yamamoto, Yuka; Sasakawa, Yasuhiro; Ichikawa, Tomotsugu; Tamiya, TakashiEuropean Journal of Nuclear Medicine and Molecular Imaging (2008), 35 (11), 2009-2017CODEN: EJNMA6; ISSN:1619-7070. (Springer)The purpose of this prospective study was to clarify the individual and combined role of l-methyl-11C-methionine-positron emission tomog. (MET-PET) and 3'-deoxy-3'-[18F]fluorothymidine (FLT)-PET in tumor detection, noninvasive grading, and assessment of the cellular proliferation rate in newly diagnosed histol. verified gliomas of different grades. Forty-one patients with newly diagnosed gliomas were investigated with MET-PET before surgery. Eighteen patients were also examd. with FLT-PET. MET and FLT uptakes were assessed by standardized uptake value of the tumor showing the max. uptake (SUVmax), and the ratio to uptake in the normal brain parenchyma (T/N ratio). All tumors were graded by the WHO grading system using surgical specimens, and the proliferation activity of the tumors were detd. by measuring the Ki-67 index obtained by immunohistochem. staining. On semiquant. anal., MET exhibited a slightly higher sensitivity (87.8%) in tumor detection than FLT (83.3%), and both tracers were 100% sensitive for malignant gliomas. Low-grade gliomas that were false neg. on MET-PET also were false neg. on FLT-PET. Although the difference of MET SUVmax and T/N ratio between grades II and IV gliomas was statistically significant (P < 0.001), there was a significant overlap of MET uptake in the tumors. The difference of MET SUVmax and T/N ratio between grades II and III gliomas was not statistically significant. Low-grade gliomas with oligodendroglial components had relatively high MET uptake. The difference of FLT SUVmax and T/N ratio between grades III and IV gliomas was statistically significant (P < 0.01). Again, the difference of FLT SUVmax and T/N ratio between grades II and III gliomas was not statistically significant. Grade III gliomas with non-contrast enhancement on MR images had very low FLT uptake. In 18 patients who underwent PET examn. with both tracers, a significant but relatively weak correlation was obsd. between the individual SUVmax of MET and FLT (r = 0.54, P < 0.05) and T/N ratio of MET and FLT (r = 0.56, P < 0.05). Total FLT uptake in the tumor had a higher correlation (r = 0.89, P < 0.001) with Ki-67 proliferation index than MET uptake (r = 0.49, P < 0.01). PET studies using MET and FLT are useful for tumor detection in newly diagnosed gliomas. However, there is no complimentary information in tumor detection with simultaneous measurements of MET- and FLT-PET in low grade gliomas. FLT-PET seems to be superior than MET-PET in noninvasive tumor grading and assessment of proliferation activity in gliomas of different grades.
- 148Ishii, K.; Ogawa, T.; Hatazawa, J.; Kanno, I.; Inugami, A.; Fujita, H.; Shimosegawa, E.; Murakami, M.; Okudera, T.; Vemura, K. High L-methyl-[11C]methionine uptake in brain abscess: A PET study. Journal of Computer Assisted Tomography. 1993, 17, 660– 661, DOI: 10.1097/00004728-199307000-00029[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3szit1GgsQ%253D%253D&md5=d7eaaaface3cf39419358ff5208ea75eHigh L-methyl-[11C]methionine uptake in brain abscess: a PET studyIshii K; Ogawa T; Hatazawa J; Kanno I; Inugami A; Fujita H; Shimosegawa E; Murakami M; Okudera T; Uemura KJournal of computer assisted tomography (1993), 17 (4), 660-1 ISSN:0363-8715.There is no expanded citation for this reference.
- 149Sonoda, Y.; Kumabe, T.; Takahashi, T.; Shirane, R.; Yoshimoto, T. Clinical usefulness of 11C-MET PET and 201Tl SPECT for differentiation of recurrent glioma from radiation necrosis. Neurol. Med. Chir. 1998, 38, 342– 348, DOI: 10.2176/nmc.38.342[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1czlsVansA%253D%253D&md5=a2b880750a3f20d4cffee0717fbf0a7eClinical usefulness of 11C-MET PET and 201T1 SPECT for differentiation of recurrent glioma from radiation necrosisSonoda Y; Kumabe T; Takahashi T; Shirane R; Yoshimoto TNeurologia medico-chirurgica (1998), 38 (6), 342-7; discussion 347-8 ISSN:0470-8105.The clinical usefulness of L-methyl-11C-methionine positron emission tomography (11C-MET PET) and thallium-201 single photon emission computed tomography (201T1 SPECT) for distinguishing glioma recurrence from radiation-induced changes was evaluated. Ten patients with lesions highly suggestive of recurrent glioma on magnetic resonance imaging underwent 11C-MET PET and 201T1 SPECT studies. Two patients were examined twice, so a total of 12 studies were performed. The clinical diagnoses were five recurrent gliomas and seven radiation necrosis. The five recurrent gliomas appeared as increased uptakes on both 11C-MET PET and 201T1 SPECT scans. Four of the seven radiation necrosis lesions also appeared as increased uptakes on the 201T1 SPECT scans. In contrast, only one radiation necrosis appeared as increased uptake on the 11C-MET PET scans. There was no significant difference in 201T1 SPECT indices between radiation necrosis and tumor recurrence, but the ratio of the differential absorption ratio of tumor tissue to that of the homologous contralateral gray matter in PET of recurrent glioma was significantly higher than that of radiation necrosis. 11C-MET PET is superior to 201T1 SPECT for the differentiation of tumor recurrence from radiation necrosis and delineation of the extent of the tumor.
- 150Nakagawa, M.; Kuwabara, Y.; Sasaki, M.; Koga, H.; Chen, T.; Kaneko, K.; Hayashi, K.; Morioka, T.; Masuda, K. 11C-methionine uptake in cerebrovascular disease: A comparison with 18F-FDG PET and 99mTc-HMPAO SPECT. Ann. Nucl. Med. 2002, 16, 207– 211, DOI: 10.1007/BF02996302[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmtlGmt7s%253D&md5=4a2d6fb0b53e44b43055382eca58c2f511C-Methionine uptake in cerebrovascular disease: a comparison with 18F-FDG PET and 99mTc-HMPAO SPECTNakagawa, Makoto; Kuwabara, Yasuo; Sasaki, Masayuki; Koga, Hirofumi; Chen, Tao; Kaneko, Kouichirou; Hayashi, Kazutaka; Morioka, Takato; Masuda, KoujiAnnals of Nuclear Medicine (2002), 16 (3), 207-211CODEN: ANMEEX; ISSN:0914-7187. (Japanese Society of Nuclear Medicine)Objectives: Carbon-11-L-methyl-methionine (11C-methionine) has been reported to be useful for evaluating brain tumors, but several other brain disorders have also shown signs of high methionine uptake. We retrospectively evaluated the significance of 11C-methionine uptake in cerebrovascular diseases, and also compared our results with those for 18F-FDG PET and 99mTc-HMPAO SPECT. Methods: Seven patients, including 3 patients with a cerebral hematoma and 4 patients with a cerebral infarction, were examd. All 7 patients underwent both 11C-methionine PET and 99mTc-HMPAO SPECT, and 6 of them underwent 18F-FDG PET. Results: A high 11C-methionine uptake was obsd. in all 3 patients with cerebral hematoma. Increased 99mTc-HMPAO uptake was obsd. in 2 out of 3 patients, and all 3 patients had decreased 18F-FDG uptake. Of 4 patients with a cerebral infarction, high 11C-methionine uptake was obsd. in 3. Increased 99mTc-HMPAO uptake was also obsd. in one patient, whereas 3 patients had decreased 18F-FDG uptake. Conclusions: We should keep in mind that high 11C-methionine uptake is frequently obsd. in cerebrovascular diseases. CVD should therefore be included in the differential diagnosis when encounting patients with a high 11C-methionine uptake.
- 151Tsuyuguchi, N.; Takami, T.; Sunada, I.; Iwai, Y.; Yamanaka, K.; Tanaka, K.; Nishikawa, M.; Ohata, K.; Torii, K.; Morino, M.; Nishio, A.; Hara, M. Methionine positron emission tomography for differentiation of recurrent brain tumor and radiation necrosis after stereotactic radiosurgery —in malignant glioma. Ann. Nucl. Med. 2004, 18, 291– 296, DOI: 10.1007/BF02984466[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpsVGit7c%253D&md5=f0f0d4bec57e1b2b076c8bdccec36b4aMethionine positron emission tomography for differentiation of recurrent brain tumor and radiation necrosis after stereotactic radiosurgery -in malignant glioma-Tsuyuguchi, Naohiro; Takami, Toshihiro; Sunada, Ichiro; Iwai, Yoshiyasu; Yamanaka, Kazuhiro; Tanaka, Kiyoaki; Nishikawa, Misao; Ohata, Kenji; Torii, Kenji; Morino, Michiharu; Nishio, Akimasa; Hara, MitsuhiroAnnals of Nuclear Medicine (2004), 18 (4), 291-296CODEN: ANMEEX; ISSN:0914-7187. (Japanese Society of Nuclear Medicine)Object: Following stereotactic radiosurgery (SRS), we examd. how to differentiate radiation necrosis from recurrent malignant glioma using positron emission tomog. (PET) with 11C-methionine (Met). Methods: Met-PET scans were obtained from 11 adult cases of recurrent malignant glioma or radiation injury, suspected on the basis of magnetic resonance images (MRI). Patients had previously been treated with SRS after primary treatment. PET images were obtained as a static scan of 10 min performed 20 min after injection of Met. We defined two visual grades (e.g., pos. or neg. Met accumulation). On Met-PET scans, the portion of the tumor with the highest accumulation was selected as the region of interest (ROI), tumor-vs.-normal ratio (TN) was defined as the ratio of av. radioisotope counts per pixel in the tumor (T), divided by av. counts per pixel in normal gray matter (N). The standardized uptake value (SUV) was calcd. over the same tumor ROI. Met-PET scan accuracy was evaluated by correlating findings with subsequent histol. anal. (8 cases) or, in cases without surgery or biopsy, by the subsequent clin. course and MR findings (3 cases). Results: Histol. examns. in 8 cases showed viable glioma cells with necrosis in 6 cases, and necrosis without viable tumor cells in 2 cases. Three other cases were considered to have radiation necrosis because they exhibited stable neurol. symptoms with no sign of massive enlargement of the lesion on follow-up MR after 5 mo. Mean TN was 1.31 in the radiation necrosis group (5 cases) and 1.87 in the tumor recurrence group (6 cases). Mean SUV was 1.81 in the necrosis group and 2.44 in the recurrence group. There were no statistically significant differences between the recurrence and necrosis groups in TN or SUV. Furthermore, we made a 2×2 factorial cross table (accumulation or no accumulation, recurrence or necrosis). From this result, the Met-PET sensitivity, specificity, and accuracy in detecting tumor recurrence were detd. to be 100%, 60%, and 82% resp. In a false pos.-case, glial fibrillary acidic protein (GFAP) immunostaining showed a pos. finding. Conclusion: There were no significant differences between recurrent malignant glioma and radiation necrosis following SRS in Met-PET. However, this study shows Met-PET has a sensitivity and accuracy for differentiating between recurrent glioma and necrosis, and presents important information for developing treatment strategies against post radiation reactions.
- 152Minamimoto, R.; Saginoya, T.; Kondo, C.; Tomura, N.; Ito, K.; Matsuo, Y.; Matsunaga, S.; Shuto, T.; Akabane, A.; Miyata, Y.; Sakai, S.; Kubota, K. Differentiation of brain tumor recurrence from post-radiotherapy necrosis with 11C-methionine PET: Visual assessment versus quantitative assessment. PLoS One 2015, 10, e0132515 DOI: 10.1371/journal.pone.0132515[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVWktrbE&md5=bd49d6e38cf3dadc0488a008cd80a74fDifferentiation of brain tumor recurrence from post-radiotherapy necrosis with 11C-methionine PET: visual assessment versus quantitative assessmentMinamimoto, Ryogo; Saginoya, Toshiyuki; Kondo, Chisato; Tomura, Noriaki; Ito, Kimiteru; Matsuo, Yuka; Matsunaga, Shigeo; Shuto, Takashi; Akabane, Atsuya; Miyata, Yoko; Sakai, Shuji; Kubota, KazuoPLoS One (2015), 10 (7), e0132515/1-e0132515/13CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Purpose The aim of this multi-center study was to assess the diagnostic capability of visual assessment in L-methyl-11C-methionine positron emission tomog. (MET-PET) for differentiating a recurrent brain tumor from radiation-induced necrosis after radiotherapy, and to compare it to the accuracy of quant. anal. Methods A total of 73 brain lesions (glioma: 1, brain metastasis: 42) in 70 patients who underwent MET-PET were included in this study. Visual anal. was performed by comparison of MET uptake in the brain lesion with MET uptake in one of four regions (around the lesion, contralateral frontal lobe, contralateral area, and contralateral cerebellar cortex). The concordance rate and logistic regression anal. were used to evaluate the diagnostic ability of visual assessment. Receiver-operating characteristic curve anal. was used to compare visual assessment with quant. assessment based on the lesion-to-normal (L/N) ratio of MET uptake. Results Interobserver and intraobserver κwere highest at 0.657 and 0.714, resp., when assessing MET uptake in the lesion compared to that in the contralateral cerebellar cortex. Logistic regression anal. showed that assessing MET uptake in the contralateral cerebellar cortex with brain metastasis was significantly related to the final result. The highest area under the receiver-operating characteristic curve (AUC) with visual assessment for brain metastasis was 0.85, showing no statistically significant difference with L/Nmax of the contralateral brain (AUC = 0.89) or with L/Nmean of the contralateral cerebellar cortex (AUC = 0.89), which were the areas that were the highest in the quant. assessment. For evaluation of gliomas, no specific candidate was confirmed among the four areas used in visual assessment, and no significant difference was seen between visual assessment and quant. assessment. Conclusion The visual assessment showed no significant difference from quant. assessment of MET-PET with a relevant cut-off value for the differentiation of recurrent brain tumors from radiation-induced necrosis.
- 153Singhal, T.; Alavi, A.; Kim, C. K. Brain: positron emission tomography tracers beyond [18F]fluorodeoxyglucose. PET Clinics. 2014, 9, 267– 276, DOI: 10.1016/j.cpet.2014.03.009[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252Fks12itA%253D%253D&md5=060f3d56739569f2e5659feb81fd97cdBrain: positron emission tomography tracers beyond [18F]fluorodeoxyglucoseSinghal Tarun; Alavi Abass; Kim Chun KPET clinics (2014), 9 (3), 267-76 ISSN:.Several PET radiopharmaceuticals beyond FDG have been used to study the physiology and pathophysiology in neurosciences. This article provides a broad overview of some of the commonly studied radiopharmaceuticals for PET imaging in selected neurologic conditions, particularly attempting to study their clinical relevance. Future studies on the use of advanced PET imaging in delineating neural pathophysiology, drug development, and altering patient management and outcomes across the disciplines of neurosciences are needed.
- 154Nihashi, T.; Dahabreh, I. J.; Terasawa, T. Diagnostic accuracy of PET for recurrent Glioma Diagnosis: A meta-analysis. AJNR Am. J. Neuroradiol. 2013, 34, 944– 950, DOI: 10.3174/ajnr.A3324[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s7gsleitw%253D%253D&md5=b578d485f684e07c374b298e0bf69e44Diagnostic accuracy of PET for recurrent glioma diagnosis: a meta-analysisNihashi T; Dahabreh I J; Terasawa TAJNR. American journal of neuroradiology (2013), 34 (5), 944-50, S1-11 ISSN:.BACKGROUND AND PURPOSE: Studies have assessed PET by using various tracers to diagnose disease recurrence in patients with previously treated glioma; however, the accuracy of these methods, particularly compared with alternative imaging modalities, remains unclear. We conducted a meta-analysis to quantitatively synthesize the diagnostic accuracy of PET and compare it with alternative imaging modalities. MATERIALS AND METHODS: We searched PubMed and Scopus (until June 2011), bibliographies, and review articles. Two reviewers extracted study characteristics, validity items, and quantitative data on diagnostic accuracy. We performed meta-analysis when ≥5 studies were available. RESULTS: Twenty-six studies were eligible. Studies were heterogeneous in treatment strategies and diagnostic criteria of PET; recurrence was typically suspected by CT or MR imaging. The diagnostic accuracies of (18)F-FDG (n = 16) and (11)C-MET PET (n = 7) were heterogeneous across studies. (18)F-FDG PET had a summary sensitivity of 0.77 (95% CI, 0.66-0.85) and specificity of 0.78 (95% CI, 0.54-0.91) for any glioma histology; (11)C-methionine PET had a summary sensitivity of 0.70 (95% CI, 0.50-0.84) and specificity of 0.93 (95% CI, 0.44-1.0) for high-grade glioma. These estimates were stable in subgroup and sensitivity analyses. Data were limited on (18)F-FET (n = 4), (18)F-FLT (n = 2), and (18)F-boronophenylalanine (n = 1). Few studies performed direct comparisons between different PET tracers or between PET and other imaging modalities. CONCLUSIONS: (18)F-FDG and (11)C-MET PET appear to have moderately good accuracy as add-on tests for diagnosing recurrent glioma suspected by CT or MR imaging. Studies comparing alternative tracers or PET versus other imaging modalities are scarce. Prospective studies performing head-to-head comparisons between alternative imaging modalities are needed.
- 155Salber, D.; Stoffels, G.; Pauleit, D.; Oros-Peusquens, A.-M.; Shah, N. J.; Klauth, P.; Hamacher, K.; Coenen, H. H.; Langen, K.-J. Differential uptake of O-(2–18F-fluoroethyl)-L-tyrosine, L-3H-methionine, and 3H-deoxyglucose in brain abscesses. J. Nucl. Med. 2007, 48, 2056– 2062, DOI: 10.2967/jnumed.107.046615[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvFSmug%253D%253D&md5=f97b2467e7200d0bc04ca01ef707abfaDifferential uptake of O-(2-18F-fluoroethyl)-L-tyrosine, L-3H-methionine, and 3H-deoxyglucose in brain abscessesSalber, Dagmar; Stoffels, Gabriele; Pauleit, Dirk; Oros-Peusquens, Anna-Maria; Shah, Nadim Jon; Klauth, Peter; Hamacher, Kurt; Coenen, Heinz Hubert; Langen, Karl-JosefJournal of Nuclear Medicine (2007), 48 (12), 2056-2062CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)The amino acid O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) has been shown to be a useful tracer for brain tumor imaging. Exptl. studies demonstrated no uptake of 18F-FET in inflammatory cells but increased uptake has been reported in single cases of human brain abscesses. To explore this inconsistency, we investigated the uptake of 18F-FET in comparison with that of L-[methyl-3H]methionine (3H-MET) and D-3H-deoxyglucose (3H-DG) in brain and calf abscesses in rats. Methods: Abscesses were induced in the brain (n = 9) and calf (n = 5) of Fisher CDF rats after inoculation of Staphylococcus aureus. Five days later, 18F-FET and 3H-MET (n = 10) or 18F-FET and 3H-DG (n = 4) were injected i.v. One hour after injection the rats were sacrificed, and the brain or calf muscle was investigated using dual-tracer autoradiog. Lesion-to-background ratios (L/B) and standardized uptake values (SUVs) were calcd. The autoradiograms were compared with histol. and immunostaining for glial fibrillary acidic protein (GFAP), CD68 for macrophages, and CD11b for microglia. Results: 18F-FET uptake in the area of macrophage infiltration and activated microglia at the rim of the brain abscesses was low (L/B, 1.5 ± 0.4). In contrast, high uptake was obsd. for 3H-MET as well as for 3H-DG (L/B, 4.1 ± 1.1 for 3H-MET vs. 3.1 ± 1.5 for 3H-DG; P < 0.01 vs. 18F-FET). Results for calf abscesses were similar. In the vicinity of the brain abscesses, slightly increased uptake was noted for 18F-FET (L/B, 1.8 ± 0.3) and 3H-MET (L/B, 1.8 ± 0.4), whereas 3H-DG distribution was normal (L/B, 1.2 ± 0.2). Anti-GFAP immunofluorescence showed a diffuse astrocytosis in those areas. Conclusion: Our results demonstrate that there is no accumulation of 18F-FET in macrophages and activated microglia in exptl. brain abscesses, whereas 3H-MET and 3H-DG exhibit high uptake in these cells. Thus, the specificity of 18F-FET for gliomas may be superior to that 3H-MET and 3H-DG. Increased 18F-FET uptake in human brain abscesses appears to be related to reactive astrocytosis.
- 156Tóth, G.; Lengyel, Z.; Balkay, L.; Salah, M. A.; Trón, L.; Tóth, C. Detection of prostate cancer with 11C-methionine positron emission tomography. J. Urol. 2005, 173, 66– 69, DOI: 10.1097/01.ju.0000148326.71981.44[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cnhvVCgsA%253D%253D&md5=5aaf093849c0ce8deab8e1f8f9ecb27eDetection of prostate cancer with 11C-methionine positron emission tomographyToth Gyorgy; Lengyel Zsolt; Balkay Laszlo; Salah Morshed A; Tron Lajos; Toth CsabaThe Journal of urology (2005), 173 (1), 66-9; discussion 69 ISSN:0022-5347.PURPOSE: We studied the detection of primary prostate cancer with positron emission tomography (PET) using C-labeled methionine (MET) in patients with increased prostate specific antigen (PSA) levels and repeatedly negative biopsies. MATERIALS AND METHODS: A total of 20 consecutive patients with increased serum PSA and negative repeat biopsies were included in the study. Patient age ranged from 52 to 75 years (average 65). PSA levels ranged from 3.49 to 28.6 ng/ml (average 9.36). Dynamic PET images were obtained from the prostate region using C-labeled MET. Suspicious accumulations of the tracer were anatomically localized using magnetic resonance images and were used as guidance during the next biopsy. RESULTS: PET was positive in 15 (75%) patients, in 7 of whom (46.7%) the next repeat biopsy verified carcinoma. The overall detection rate was 35% (7 of 20) and 46.7% (7 of 15) in the whole group and in the positive PET group, respectively. All 5 of 5 patients with negative MET PET had negative biopsies. CONCLUSIONS: MET PET of the prostate with short dynamic scanning and multicore biopsy is a useful method to ensure a high detection rate of prostate cancer in patients with increased PSA and repeat negative biopsies.
- 157Jana, S.; Blaufox, M. D. Nuclear medicine studies of the prostate, testes, and bladder. Semin. Nucl. Med. 2006, 36, 51– 72, DOI: 10.1053/j.semnuclmed.2005.09.001[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnntVaguw%253D%253D&md5=bc58a76171ac93293e2ecc5ad2edaf90Nuclear medicine studies of the prostate, testes, and bladderJana Suman; Blaufox M DonaldSeminars in nuclear medicine (2006), 36 (1), 51-72 ISSN:0001-2998.During the last decade, there has been a significant advancement in imaging of urologic diseases. Transrectal ultrasound (TRUS), computerized tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) are still experiencing new developments in urology. Despite these many technological advances, the initial diagnostic procedure for a patient with suspected prostate cancer (PC) is multiple site blind prostate biopsies. There is a need for a noninvasive metabolic imaging modality to direct the site of biopsy to decrease the sampling error. MRS seems promising but as it is a costly and more time-consuming test, further studies are needed to evaluate its clinical utility. Currently, PET does not play any role to direct biopsy. Acetate and choline appear to be better tracers than FDG for the detection of a prostate lesion, however, further well-organized studies are needed before any of these agents can be used clinically. Incidental detection of intense focal uptake in the prostate during whole body PET scanning should be evaluated with prostate-specific antigen (PSA) and TRUS-guided biopsy. Although FDG is inferior to other tracers for primary staging, it may be useful in selected patients with suspected high-grade cancer. The role of ProstaScint scan is still controversial for detection of recurrent PC. This study may be helpful for evaluating nodal metastases when PSA is elevated and bone scan is negative. Bone scan remains the study of choice when bone metastases are suspected (PSA>15-20 ng/mL+/-bone pain). Acetate and choline provide better accuracy than FDG in the detection of local soft tissue disease, nodal involvement, and distant metastases. High FDG uptake may be indicative of more aggressive and possibly androgen-independent disease. PET/CT with any of the above PET tracers will most likely be preferred to the PET scan alone due to better localization of a hot lesion in PET/CT. Nuclear medicine studies also have been used to evaluate acute scrotum and testicular neoplasms. Scrotal scintigraphy has lost its popularity to Doppler ultrasound in the evaluation of the acute scrotum. In testicular tumors, FDG-PET appears to be superior to conventional imaging modalities in initial staging, detection of residual/recurrence, and monitoring treatment response. Tumor markers after treatment occasionally are elevated and cannot locate the site of recurrence, FDG-PET can play a very important role in this regard. Nuclear medicine studies also have been used to evaluate diseases of the urinary bladder. Radionuclide cystography is more sensitive and has less than 1/20 the radiation exposure of the conventional contrast enhanced micturating cystourethrogram (MCU). However, the utility of FDG-PET in the evaluation of bladder cancer seems to be limited to the evaluation of distant metastases. 11C-Methionine and choline may be a better option for local and nodal disease due to their negligible excretion in the urine.
- 158Deng, H.; Tang, X.; Wang, H.; Tang, G.; Wen, F.; Shi, X.; Yi, C.; Wu, K.; Meng, Q. S-11C-methyl-L-cysteine: A new amino acid PET tracer for cancer imaging. J. Nucl. Med. 2011, 52, 287– 293, DOI: 10.2967/jnumed.110.081349[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisF2ku7Y%253D&md5=e10679f12a5b5b1756dad6b9d6c655edS-11C-methyl-L-cysteine: a new amino acid PET tracer for cancer imagingDeng, Huaifu; Tang, Xiaolan; Wang, Hongliang; Tang, Ganghua; Wen, Fuhua; Shi, Xinchong; Yi, Chang; Wu, Kening; Meng, QuanfeiJournal of Nuclear Medicine (2011), 52 (2), 287-293CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)S-11C-methyl-L-cysteine (11C-MCYS), an analog of S-11C-methyl-L-methionine (11C-MET), can potentially serve as an amino acid PET tracer for tumor imaging. The aim of this study was to investigate the radiosynthesis and perform a biol. evaluation of 11C-MCYS as a tumor imaging tracer. The results of the first human PET study are reported. Methods: 11C-MCYS was prepd. by 11C-methylation of the precursor L-cysteine with 11CH3I and purifn. on com. C18 cartridges. In vitro competitive inhibition expts. were performed with Hepa1-6 hepatoma cell lines, and biodistribution of 11C-MCYS was detd. in normal mice. The incorporation of 11C-MCYS into tissue proteins was investigated. In vivo 11C-MCYS uptake studies were performed on hepatocellular carcinoma-bearing nude mice and inflammation models and compared with 11C-MET PET and 18F-FDG PET. In a human PET study, a patient with a recurrence of glioma after surgery was examd. with 11C-MCYS PET and 18F-FDG PET. Results: The uncorrected radiochem. yield of 11C-MCYS from 11CH3I was more than 50% with a synthesis time of 2 min, the radiochem. purity of 11C-MCYS was more than 99%, and the enantiomeric purity was more than 90%. In vitro studies showed that 11C-MCYS transport was mediated through transport system L. Biodistribution studies demonstrated high uptake of 11C-MCYS in the liver, stomach wall, and heart and low uptake of 11C-MCYS in the brain. There was higher accumulation of 11C-MCYS in the tumor than in the muscles. The tumor-to-muscle and inflammatory lesion-to-muscle ratios were 7.27 and 1.62, resp., for 11C-MCYS, 5.08 and 3.88, resp., for 18F-FDG, and 4.26 and 2.28, resp., for 11C-MET at 60 min after injection. Almost no 11C-MCYS was incorporated into proteins. For the patient PET study, high uptake of 11C-MCYS with true-pos. results, but low uptake of 18F-FDG with false-neg. results, was found in the recurrent glioma. Conclusion: Automated synthesis of 11C-MCYS is easy to perform. 11C-MCYS is superior to 11C-MET and 18F-FDG in the differentiation of tumor from inflammation and seems to have potential as an oncol. PET tracer for the diagnosis of solid tumors.
- 159Huang, T.; Tang, G.; Wang, H.; Nie, D.; Tang, X.; Liang, X.; Hu, K.; Yi, C.; Yao, B.; Tang, C. Synthesis and preliminary biological evaluation of S-11C-methyl-D-cysteine as a new amino acid PET tracer for cancer imaging. Amino Acids 2015, 47, 719– 727, DOI: 10.1007/s00726-014-1899-4[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFCrurjI&md5=877ce201aac02f6b8ea75d68c36dfea6Synthesis and preliminary biological evaluation of S-11C-methyl-D-cysteine as a new amino acid PET tracer for cancer imagingHuang, Tingting; Tang, Ganghua; Wang, Hongliang; Nie, Dahong; Tang, Xiaolan; Liang, Xiang; Hu, Kongzhen; Yi, Chang; Yao, Baoguo; Tang, CaihuaAmino Acids (2015), 47 (4), 719-727CODEN: AACIE6; ISSN:0939-4451. (Springer-Verlag GmbH)S-11C-methyl-L-cysteine (LMCYS) is an attractive amino acid tracer for clin. tumor positron emission tomog. (PET) imaging. D-Isomers of some radiolabeled amino acids are potential PET tracers for tumor imaging. In this work, S-11C-methyl-D-cysteine (DMCYS), a D-amino acid isomer of S-11C-methyl-cysteine for tumor imaging was developed and evaluated. DMCYS was prepd. by 11C-methylation of the precursor D-cysteine, with an uncorrected radiochem. yield over 50 % from 11CH3I within a total synthesis time from 11CO2 about 12 min. In vitro competitive inhibition studies showed that DMCYS uptake was primarily transported through the Na+-independent system L, and also the Na+-dependent system B0,+ and system ASC, with almost no system A. In vitro incorporation expts. indicated that almost no protein incorporation was found in Hepa 1-6 hepatoma cell lines. Biodistribution studies demonstrated higher uptake of DMCYS in pancreas and liver at 5 min post-injection, relatively lower uptake in brain and muscle, and faster radioactivity clearance from most tissues than those of L-isomer during the entire observation time. In the PET imaging of S180 fibrosarcoma-bearing mice and turpentine-induced inflammatory model mice, 2-18F-fluoro-2-deoxy-D-glucose (FDG) exhibited significantly high accumulation in both tumor and inflammatory lesion with low tumor-to-inflammation ratio of 1.40, and LMCYS showed low tumor-to-inflammation ratio of 1.64 at 60 min post-injection. By contrast, DMCYS showed moderate accumulation in tumor and very low uptake in inflammatory lesion, leading to relatively higher tumor-to-inflammation ratio of 2.25 than 11C-methyl-L-methionine (MET) (1.85) at 60 min post-injection. Also, PET images of orthotopic transplanted glioma models demonstrated that low uptake of DMCYS in normal brain tissue and high uptake in brain glioma tissue were obsd. The results suggest that DMCYS is a little better than the corresponding L-isomers as a potential PET tumor-detecting agent and is superior to MET and FDG in the differentiation of tumor from inflammation.
- 160Sutinen, E.; Jyrkkiö, S.; Alanen, K.; Någren, K.; Minn, H. Uptake of [N-methyl-11C]α-methylaminoisobutyric acid in untreated head and neck cancer studied by PET. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 72– 77, DOI: 10.1007/s00259-002-1010-3[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpsV2iu70%253D&md5=4cb3ba676b42b451c1885cd1719fac6dUptake of [N-methyl-11C]α-methylaminoisobutyric acid in untreated head and neck cancer studied by PETSutinen, Eija; Jyrkkioe, Sirkku; Alanen, Kalle; Nagren, Kjell; Minn, HeikkiEuropean Journal of Nuclear Medicine and Molecular Imaging (2003), 30 (1), 72-77CODEN: EJNMA6; ISSN:1619-7070. (Springer-Verlag)Amino acid transport system A is expressed strongly in neoplastic cells. [N-methyl-11C]α-Methylaminoisobutyric acid (11C-MeAIB) is a recently developed tracer for PET studies on system A amino acid transport. 11C-MeAIB is a metabolically stable amino acid analog which is transported from plasma into the tissue by system A. This study evaluated the kinetics of 11C-MeAIB uptake from plasma into tumor tissue and normal tissues in 13 patients with untreated head and neck cancer. 11C-MeAIB uptake in tumor was compared with histol. grade and proliferative activity. Tracer uptake was quantitated by calcg. the standardized uptake values (SUVs) and the kinetic influx consts. (Ki) using graphical anal. All tumors accumulated 11C-MeAIB and were visualised clearly. In the graphical anal., linear plots were achieved; the mean Ki value of tumor was 0.056±0.026 min-1, and the mean SUV was 6.1±2.7. A close correlation between graphically obtained Ki and semi-quant. SUV in tumors was found (r=0.887, P=0.00005). We could not demonstrate a correlation between the uptake of 11C-MeAIB and the grade of malignancy or the proliferative index, as assessed using Ki-67 immunohistochem. assay. Head and neck cancer can be effectively imaged with 11C-MeAIB PET. 11C-MeAIB showed active and rapid transport into tumor tissue and salivary glands. Further studies on the applicability of 11C-MeAIB PET for radiation treatment planning in the head and neck region and the regulation of system A amino acid transport under different metabolic states are warranted.
- 161Nishii, R.; Higashi, T.; Kagawa, S.; Kishibe, Y.; Takahashi, M.; Yamauchi, H.; Motoyama, H.; Kawakami, K.; Nakaoku, T.; Nohara, J.; Okamura, M.; Watanabe, T.; Nakatani, K.; Nagamachi, S.; Tamura, S.; Kawai, K.; Kobayashi, M. Diagnostic usefulness of an amino acid tracer, α-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB), in the PET diagnosis of chest malignancies. Ann. Nucl. Med. 2013, 27, 808– 821, DOI: 10.1007/s12149-013-0750-4[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVWlu7rL&md5=b4bb81af65105b1ee8814d32518e81f5Diagnostic usefulness of an amino acid tracer, α-[N-methyl-11C|-methylaminoisobutyric acid (11C-MeAIB), in the PET diagnosis of chest malignanciesNishii, Ryuichi; Higashi, Tatsuya; Kagawa, Shinya; Kishibe, Yoshihiko; Takahashi, Masaaki; Yamauchi, Hiroshi; Motoyama, Hideki; Kawakami, Kenzo; Nakaoku, Takashi; Nohara, Jun; Okamura, Misato; Watanabe, Toshiki; Nakatani, Koichi; Nagamachi, Shigeki; Tamura, Shozo; Kawai, Keiichi; Kobayashi, MasatoAnnals of Nuclear Medicine (2013), 27 (9), 808-821CODEN: ANMEEX; ISSN:0914-7187. (Springer Japan)Objectives: Although positron emission tomog. (PET) using [18F]-fluoro-2-deoxy-D-glucose (18F-FDG) is established as one of the first-choice imaging modalities in the diagnosis of chest malignancies, there are several problems to solve in clin. practice, such as false pos. uptake in inflammatory diseases. The aim of this study was to evaluate the clin. usefulness of an amino acid tracer, α-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB), in the diagnosis of chest malignancies, in combination with 18F-FDG. Setting: Fifty-nine cases (57 patients, 66 ± 12 years old) who consulted to our institution for the wish to receive differential diagnosis of chest diseases were included. Purpose of the studies were as follows: differential diagnosis of newly developed lung nodules, n = 22; newly developed mediastinal lesions, n = 20; and both, n = 17 (including lung cancer: n = 19, lymphoma: n = 1, other cancers: n = 2, sarcoidosis: n = 15, non-specific inflammation: n = 18, other inflammatory: n = 4, resp.). Whole-body static PET or PET/CT scan was performed 20 and 50 min after the IV injection of 11C-MeAIB and 18F-FDG, resp. Results: 11C-MeAIB uptake of malignant and benign lesions was statistically different both in pulmonary nodules (p < 0.005) and in mediastinal lesions (p < 0.0005). In visual differential diagnosis, 11C-MeAIB showed higher results (specificity: 73 %, accuracy: 81 %), compared to those in 18F-FDG (60, 73 %, resp.). In cases of sarcoidosis, 11C-MeAIB showed higher specificity (80 %) with lower uptake (1.8 ± 0.7) in contrast to the lower specificity (60 %) with higher uptake of 18F-FDG (7.3 ± 4.5). Conclusions: 11C-MeAIB PET/CT was useful in the differential diagnosis of pulmonary and mediastinal mass lesions found on CT. 11C-MeAIB PET or PET/CT showed higher specificity than that of 18F-FDG PET/CT in differentiating between benign and malignant disease. Our data suggest that the combination of 18F-FDG and 11C-MeAIB may improve the evaluation of chest lesions, when CT and 18F-FDG PET/CT are equivocal.
- 162Washburn, L. C.; Sun, T. T.; Anon, J. B.; Hayes, R. L. Effect of structure on tumor specificity of alicyclic alpha-amino acids. Cancer Res. 1978, 38, 2271– 2273[PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXmtFWhs7o%253D&md5=f1b3a75c68924d8811527eca033b2778Effect of structure on tumor specificity of alicyclic α-amino acidsWashburn, Lee C.; Sun, Tan Tan; Anon, Jack B.; Hayes, Raymond L.Cancer Research (1978), 38 (8), 2271-3CODEN: CNREA8; ISSN:0008-5472.The selective affinity of 1-aminocyclopentanecarboxylic-carboxyl-14C acid (I) for tumor tissue led to the study of the tumor-localizing characteristics of a series of alicyclic α-amino acid analogs of I. The tissue distributions of 1-aminocyclopropanecarboxylic-14C acid, 1-aminocyclobutanecarboxylic-14C acid (II), 1-aminocyclohexanecarboxylic-14C acid, 1-amino-2-methylcyclopentanecarboxylic-14C acid, and 1-amino-3-methylcyclopentanecarboxylic-14C acid were compared with that of I in Buffalo rats bearing Morris 5123C hepatomas. I and II had higher tumor/nontumor concn. ratios than the other 4 amino acids. II generally had higher tumor/nontumor ratios than did I, significantly so for muscle, kidney, and testis, and marginally so for blood. Evidently, II may be a better agent than I for tumor imaging by positron tomog.
- 163Vis, K. D.; Schelstraete, K.; Deman, J.; Vermeulen, F. L.; Sambre, J.; Goethals, P.; Haver, D. V.; Slegers, G.; Vandecasteele, C.; Schryver, A. D. Clinical comparison of 11C-ACPC (aminocyclopentane carboxylic acid) and 13N-ammonia as tumour tracers. Acta Oncol. 1987, 26, 105– 111, DOI: 10.3109/02841868709091749
- 164Öberg, K.; Castellano, D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev. 2011, 30 (S1), 3– 7, DOI: 10.1007/s10555-011-9292-1[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3msVKqtw%253D%253D&md5=3896b1208cae508c31e3263c907aef85Current knowledge on diagnosis and staging of neuroendocrine tumorsOberg Kjell; Castellano DanielCancer metastasis reviews (2011), 30 Suppl 1 (), 3-7 ISSN:.Neuroendocrine tumors (NETs) consist of a heterogeneous group of malignancies with various clinical presentations and growth rates. The incidence has been estimated to 2.5-5 per 100,000 people per year and prevalence of 35 per 100,000. The largest group is the gastroenteropancreatic NETs. Small intestinal NETs are the most common followed by pancreatic NETs in the gastrointestinal tract. A classification system (World Health Organization) was established in year 2000 and recently updated in 2010, taking into consideration the histopathology and tumor biology of the tumors. To further refine the classification a "tumor node metastasis" staging has been suggested by the European Neuroendocrine Tumor Society. The same organization has also proposed a grading system (G1, G2, and G3). The diagnosis of a NET is based on histopathology on tumor specimens, circulating biomarkers as well as imaging. Traditional radiology, such as computerized tomography and magnetic resonance imaging, is still the basis but is complemented with somatostatin receptor scintigraphy and positron emission tomography with specific isotopes such (68)Ga-DOTA-octreotate, F18-dopamine, or C11-5 hydroxytryptamine. Molecular imaging will increase in importance in the near future. There is still an unmet need for more sensitive biomarkers for diagnosis and follow-up.
- 165Toumpanakis, C.; Kim, M. K.; Rinke, A.; Bergestuen, D. S.; Thirlwell, C.; Khan, M. S.; Salazar, R.; Oberg, K. Combination of cross-sectional and molecular imaging studies in the localization of gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology 2014, 99, 63– 74, DOI: 10.1159/000358727[Crossref], [PubMed], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1WqtrfI&md5=a63f62b0b8ccadd1f9cec8bd7429089dCombination of Cross-Sectional and Molecular Imaging Studies in the Localization of Gastroenteropancreatic Neuroendocrine TumorsToumpanakis, Christos; Kim, Michelle K.; Rinke, Anja; Bergestuen, Deidi S.; Thirlwell, Christina; Khan, Mohid S.; Salazar, Ramon; Oberg, KjellNeuroendocrinology (2014), 99 (2), 63-74CODEN: NUNDAJ; ISSN:0028-3835. (S. Karger AG)A review. Mol. imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiol. for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET det. which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available mol. imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clin. scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 (68Ga)-DOTA positron emission tomog. (PET) techniques may replace SRS in the future, not only because of their tech. advantages, but also because they are superior in patients with small-vol. disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 (11C)-5-hydroxy-L-tryptophan (5-HTP) PET and 18F-dihydroxyphenylalanine (18F-DOPA) PET are new mol. imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of 68Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 (18F)-fluorodeoxyglucose (18F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, 18F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, 18F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining mol. imaging techniques (e.g. 18F-FDG PET and 68Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned mol. imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up.
- 166Orlefors, H.; Sundin, A.; Garske, U.; Juhlin, C.; Oberg, K.; Skogseid, B.; Langstrom, B.; Bergstrom, M.; Eriksson, B. Whole-body 11C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: Comparison with somatostatin receptor scintigraphy and computed tomography. J. Clin. Endocrinol. Metab. 2005, 90, 3392– 3400, DOI: 10.1210/jc.2004-1938[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkvFCltrc%253D&md5=284ac4d7911dc287630f4e2864d7b42bWhole-body 11C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: Comparison with somatostatin receptor scintigraphy and computed tomographyOrlefors, H.; Sundin, A.; Garske, U.; Juhlin, C.; Oberg, K.; Skogseid, B.; Langstrom, B.; Bergstrom, M.; Eriksson, B.Journal of Clinical Endocrinology and Metabolism (2005), 90 (6), 3392-3400CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)Neuroendocrine tumors (NETs) can be small and situated almost anywhere throughout the body. Our objective was to investigate whether whole-body (WB) positron emission tomog. (PET) with 11C-5-hydroxytryptophan (5-HTP) can be used as a universal imaging technique for NETs and to compare this technique with established imaging methods. Forty-two consecutive patients with evidence of NET and a detected lesion on any conventional imaging (six bronchial, two foregut, 16 midgut, and two thymic carcinoids; one ectopic Cushing's syndrome; four gastrinomas; one insulinoma; six nonfunctioning endocrine pancreatic tumors; one gastric carcinoid, one paraganglioma; and two endocrine-differentiated pancreatic carcinomas) were studied. The WB-11C-5-HTP-PET examns. were compared with WB-computed tomog. (CT) and somatostatin receptor scintigraphy (SRS). Tumor lesions were imaged with PET in 95% of the patients. In 58% of the patients, PET could detect more lesions than SRS and CT and equal nos. in 34%, whereas in three cases, SRS or CT showed more lesions. In 84% (16 of 19 patients), PET could visualize the primary tumor compared with 47 and 42% for SRS and CT, resp. The surgically removed PET-pos. primary tumor sizes were 6-30 mm. To conclude, this study indicates that WB-11C-5-HTP-PET can be used as a universal imaging method for detection of NETs. This study also shows that WB-11C-HTP-PET is sensitive in imaging small NET lesions, such as primary tumors, and can in a majority of cases image significantly more tumor lesions than SRS and CT.
- 167Eriksson, B.; Orlefors, H.; Oberg, K.; Sundin, A.; Bergström, M.; Långström, B. Developments in PET for the detection of endocrine tumours. Best Pract. Res. Clin. Endocrinol. Metab. 2005, 19, 311– 324, DOI: 10.1016/j.beem.2004.11.001[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M7jtFygug%253D%253D&md5=db0a61fee0d04a8e08ee688fc6454d45Developments in PET for the detection of endocrine tumoursEriksson B; Orlefors H; Oberg K; Sundin A; Bergstrom M; Langstrom BBest practice & research. Clinical endocrinology & metabolism (2005), 19 (2), 311-24 ISSN:1521-690X.Positron emission tomography (PET) supplies a range of labelled compounds to be used for the characterization of tumour biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow-up, and clinical research. (18)F-fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology, reflecting increased expression of glucose transporters in cancerous tissue. This tracer, however, does not show sufficient uptake in well-differentiated tumours such as neuroendocrine tumours. Endocrine tumours have the unique characteristics of taking up and decarboxylating amine precursors. These so-called APUD characteristics offer highly specific targets for PET tracers. Using this approach, radiopharmaceuticals such as [(11)C]-5-hydroxytryptophan and [(11)C]-L-dihydroxyphenylalanine for localization of carcinoid and endocrine pancreatic tumours, 6-[(18)F]-fluorodopamine and [(11)C]-hydroxyephedrine for phaeochromocytomas, and [(11)C]-metomidate for adrenal cortical tumours have been developed. Functional imaging with PET using these compounds is now being employed to complement rather than replace other imaging modalities. Development of new PET radiopharmaceuticals may in the future allow in vivo detection of tumour biological properties, such as malignant potential and responsiveness to treatment.
- 168Bjurling, P.; Watanabe, Y.; Tokushige, M.; Oda, T.; Långström, B. Syntheses of β-11C-labelled L-tryptophan and 5-hydroxy-L-tryptophan using a multi-enzymatic reaction route. J. Chem. Soc., Perkin Trans. 1 1989, 7, 1331– 1334, DOI: 10.1039/P19890001331
- 169Pruim, J.; Willemsen, A. T.; Molenaar, W. M.; van Waarde, A.; Paans, A. M.; Heesters, M. A.; Go, K. G.; Visser, G. M.; Franssen, E. J.; Vaalburg, W. Brain Tumors: L-[1-C-11]tyrosine PET for visualization and quantification of protein synthesis rate. Radiology 1995, 197, 221– 226, DOI: 10.1148/radiology.197.1.7568827[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXptlaksL4%253D&md5=76631465424928518d63ab69d41bfc7aBrain tumors: L-[1-C-11]tyrosine PET for visualization and quantification of protein synthesis ratePruim, Jan; Willemsen, Antoon T. M.; Molenaar, Willemina M.; van Waarde, Aren; Paans, Anne M. J.; Heesters, Martinus A. A. M.; Go, K. Gwan; Visser, Gerben M.; Franssen, Eric J. F.; Vaalburg, WillemRadiology (Oak Brook, Illinois) (1995), 197 (1), 221-6CODEN: RADLAX; ISSN:0033-8419. (Radiological Society of North America)Positron emission tomog. (PET) with the amino acid tracer L-[1-C-11]-tyrosine was evaluated in 27 patients with primary and recurrent brain tumors. Patients underwent either static (n = 14) or dynamic PET (n = 13), with quantification of protein synthesis rate (PSR) and tumor-to-background ratio. Findings were compared with histol. findings. Primary brain tumor was proved in 22 patients histol., as well as metastatic cancer of unknown origin, primary non-Hodgkin lymphoma, meningioma, atypical infarction, and vasculitis in one patient each. At PET, 20 of 22 primary tumors, the metastasis, and non-Hodgkin lymphoma were correctly depicted. A false-pos. finding was obtained with the infarction, and the meningioma and vasculitis were not depicted. The calcd. sensitivity was 92%; specificity, 67%; and accuracy, 89%. There were no statistically significant relationships between histol. findings, PSR, and tumor-to-background ratio. L-[1-C-11]-tyrosine is a valid tracer for diagnosis of brain tumors and allowed quantification of PSR.
- 170Kole, A. C.; Nieweg, O. E.; Pruim, J.; Paans, A. M.; Plukker, J. T.; Hoekstra, H. J.; Schraffordt Koops, H.; Vaalburg, W. Standardized uptake value and quantification of metabolism for breast cancer imaging with FDG and L-[1–11C]tyrosine PET. J. Nucl. Med. 1997, 38, 692– 696[PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2szhsVSrtQ%253D%253D&md5=4eb88a689e5ccf0018ef27d767e98fc0Standardized uptake value and quantification of metabolism for breast cancer imaging with FDG and L-[1-11C]tyrosine PETKole A C; Nieweg O E; Pruim J; Paans A M; Plukker J T; Hoekstra H J; Schraffordt Koops H; Vaalburg WJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1997), 38 (5), 692-6 ISSN:0161-5505.UNLABELLED: The aims of the study were to compare the value of L-[1-11C]tyrosine (TYR) and [IBF]fluoro-2-deoxy-D-glucose (FDG) as tumor tracers in patients with breast cancer, to investigate the correlation between quantitative values and standardized uptake values (SUVs) and to estimate the value of SUVs for the evaluation of therapy. METHODS: Eleven patients with one or more malignant breast lesions and two patients with one or more benign breast tumors were studied with TYR and FDG. Doses of 300 MBq of TYR and 230 MBq of FDG were given intravenously. All PET sessions were performed using a Siemens ECAT 951/31 camera. Of 10 malignant tumors and the 3 benign lesions, glucose consumption and protein synthesis rate were quantified. All lesions were studied using SUVs based on body weight, body surface area and lean body mass, with and without correction for plasma glucose or tyrosine levels. RESULTS: All malignant tumors were visualized with both FDG and TYR, but the visual contrast was better with FDG. Increased uptake of the tracers was seen in patients with fibrocystic tissue and complicated the visual assessment and the outlining of tumor tissue. Uptake in fibrocystic disease was more prominent with FDG than with TYR. No difference in tumor/nontumor ratio between the two tracers could be established. FDG showed a false-positive result in one benign lesion. No major differences between the SUVs as defined above were found, although the best correlation between glucose consumption and the SUV was observed when the SUV was based on body surface area and corrected for plasma glucose level (r = 0.85-0.87). The SUV based on lean body mass was found to correlate best with protein synthesis rate (r = 0.83-0.94). CONCLUSION: In this group of patients, TYR appears to be a better tracer than FDG for breast cancer imaging, because of lower uptake in fibrocystic disease. SUVs correlate well with quantitative values, but future studies must determine whether treatment evaluation is also reliable with SUVs.
- 171Plaat, B.; Kole, A.; Mastik, M.; Hoekstra, H.; Molenaar, W.; Vaalburg, W. Protein synthesis rate measured with L-[1–11C]tyrosine positron emission tomography correlates with mitotic activity and MIB-1 antibody-detected proliferation in human soft tissue sarcomas. Eur. J. Nucl. Med. Mol. Imaging 1999, 26, 328– 332, DOI: 10.1007/s002590050394
- 172Braams, J. W.; Pruim, J.; Nikkels, P. G.; Roodenburg, J. L.; Vaalburg, W.; Vermey, A. Nodal spread of squamous cell carcinoma of the oral cavity detected with PET-tyrosine, MRI and CT. J. Nucl. Med. 1996, 37, 897– 901[PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK28zgtVentQ%253D%253D&md5=1a9c95b4de9ce0c4855b11586b5a0533Nodal spread of squamous cell carcinoma of the oral cavity detected with PET-tyrosine, MRI and CTBraams J W; Pruim J; Nikkels P G; Roodenburg J L; Vaalburg W; Vermey AJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1996), 37 (6), 897-901 ISSN:0161-5505.UNLABELLED: The uptake of L-1-[11C]-tyrosine (TYR) in cervical lymph nodes of eleven patients with squamous-cell carcinoma (SCC) of the oral cavity was studied with PET to detect lymphogenic metastases. METHODS: The TYR-PET results were compared with clinical, MRI, CT, histopathologic findings and historical data of patients studied with FDG. Sensitivity, specificity, accuracy and the positive and negative predictive values were calculated. RESULTS: TYR-PET had sensitivity of 83% and a specificity of 95%. In contrast, the sensitivity and specificity for MRI were 33% and 96%, respectively. The sensitivity and specificity for CT were 55% and 91%, respectively. TYR-PET results compared favorably with FDG. CONCLUSION: With TYR-PET, SCC metastases of the oral cavity can be visualized with high sensitivity and specificity. TYR-PET can be an additional tool for further evaluation of neck malignancies.
- 173Juhász, C.; Muzik, O.; Chugani, D. C.; Chugani, H. T.; Sood, S.; Chakraborty, P. K.; Barger, G. R.; Mittal, S. Differential kinetics of α-[11C]methyl-L-tryptophan on PET in low-grade brain tumors. J. Neuro-Oncol. 2011, 102, 409– 415, DOI: 10.1007/s11060-010-0327-1[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlslCntb0%253D&md5=651dd82c2ef47d8a2fb4d98be3efb820Differential kinetics of α-[11C]methyl-l-tryptophan on PET in low-grade brain tumorsJuhasz, Csaba; Muzik, Otto; Chugani, Diane C.; Chugani, Harry T.; Sood, Sandeep; Chakraborty, Pulak K.; Barger, Geoffrey R.; Mittal, SandeepJournal of Neuro-Oncology (2011), 102 (3), 409-415CODEN: JNODD2; ISSN:0167-594X. (Springer)Increased tryptophan metab. via the kynurenine pathway is a major mechanism of tumor immuno-resistance. α-[11C]Methyl-l-tryptophan (AMT) is a positron emission tomog. (PET) tracer for tryptophan catabolism, and increased AMT uptake has been demonstrated in brain tumors. In this study we evaluated the use of AMT PET for detection of low-grade gliomas and glioneuronal tumors, and detd. if kinetic parameters of AMT uptake can differentiate among tumor types. AMT PET images were obtained in 23 patients with newly diagnosed low-grade brain tumors (WHO grade II gliomas and WHO grade I dysembryoplastic neuroepithelial tumors [DNETs]). Kinetic variables, including the unidirectional uptake rate (K-complex) and vol. of distribution (VD; which characterizes tracer transport), were measured using a graphical approach from tumor dynamic PET and blood-input data, and metabolic rates () were also calcd. These values as well as tumor/cortex ratios were compared across tumor types. AMT PET showed increased tumor/cortex K-complex (n = 16) and/or VD ratios (n = 15) in 21/23 patients (91%), including 11/13 tumors with no gadolinium enhancement on MRI. No increases in AMT were seen in an oligodendroglioma and a DNET. Astrocytomas and oligoastrocytomas showed higher tumor/cortex ratios (1.66 ± 0.46) than oligodendrogliomas (0.96 ± 0.21; P = 0.001) and DNETs (0.75 ± 0.39; P < 0.001). These results demonstrate that AMT PET identifies most low-grade gliomas and DNETs by high uptake, even if these tumors are not contrast-enhancing on MRI. Kinetic anal. of AMT uptake shows significantly higher tumor/cortex tryptophan metabolic ratios in astrocytomas and oligoastrocytomas in comparison with oligodendrogliomas and DNETs.
- 174Diksic, M.; Nagahiro, S.; Chaly, T.; Sourkes, T. L.; Yamamoto, Y. L.; Feindel, W. Serotonin synthesis rate measured in living dog brain by positron emission tomography. J. Neurochem. 1991, 56, 153– 162, DOI: 10.1111/j.1471-4159.1991.tb02575.x[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlsFymtg%253D%253D&md5=0c131f09f5438dc40dbf80c6540ae92bSerotonin synthesis rate measured in living dog brain by positron emission tomographyDiksic, M.; Nagahiro, S.; Chaly, T.; Sourkes, T. L.; Yamamoto, Y. L.; Feindel, W.Journal of Neurochemistry (1991), 56 (1), 153-62CODEN: JONRA9; ISSN:0022-3042.In vivo measurements by positron emission tomog. of the brain 5-HT synthesis rates in the normal dog, in the dog with increased plasma tryptophan concn., and in the dog under different arterial O tensions are described. This method permits repeated measurements in the same brain for the first time. An increase in the plasma tryptophan concn. from 16.6 to 191.5 and then to 381 μM resulted in close to a linear increase in the brain 5-HT synthesis rate. When PaO2 was raised from 76 to 106 mm Hg, the rate of 5-HT synthesis in the dog brain increased from 39 to 54 pmol/g/min. The ests. of the Michaelis-Menten consts., Kmapp and Vmax, for the transport of tryptophan through the blood-brain barrier are 303 μM and 63 nmol/g/min, resp.
- 175Diksic, M.; Nagahiro, S.; Sourkes, T. L.; Yamamoto, Y. L. A new method to measure brain serotonin synthesis in vivo. I. theory and basic data for a biological model. J. Cereb. Blood Flow Metab. 1990, 10, 1– 12, DOI: 10.1038/jcbfm.1990.1[Crossref], [PubMed], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhslagu7Y%253D&md5=520e54d1be3e4e699996a58cbb63f5ddA new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological modelDiksic, M.; Nagahiro, S.; Sourkes, T. L.; Yamamoto, Y. L.Journal of Cerebral Blood Flow and Metabolism (1990), 10 (1), 1-12CODEN: JCBMDN; ISSN:0271-678X.An autoradiog. method to measure the in vivo rate of serotonin synthesis in rat brain is described. The method is based on the use of the L-tryptophan analog α-methyl-L-tryptophan (α-MTrp), which is converted in vivo into α-methylserotonin (α-M5HT). Since α-M5HT is not a substrate for monoamine oxidase, it is accumulated in the brain tissue. Data are presented to confirm time-dependent conversion of α-MTrp into α-M5HT in the dorsal raphe nucleus and also in the pineal body, an organ outside the blood-brain barrier. Washing of brain slices in 10% TCA resulted in <3% incorporation of α-MTrp into brain proteins. The rates of synthesis are calcd. in several grossly dissected brain structures by using tracer kinetics and a 3-compartment biol. model. The half-life of the precursor pool is ∼20 min. The rate of serotonin synthesis is highest in the pineal body.
- 176Diksic, M.; Tohyama, Y.; Takada, A. Brain net unidirectional uptake of alpha-[14C]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp. Neurochem. Res. 2000, 25, 1537– 1546, DOI: 10.1023/A:1026654116999[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovFyhtrs%253D&md5=f170a9fc6e5df59e7b7e78a06f4165b4Brain net unidirectional uptake of α-[14C]methyl-L-tryptophan (α-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and α-MTrpDiksic, Mirko; Tohyama, Yoshihiro; Takada, AkiraNeurochemical Research (2000), 25 (12), 1537-1546CODEN: NEREDZ; ISSN:0364-3190. (Kluwer Academic/Plenum Publishers)The uptake and trapping consts. for labeled tryptophan (Trp) via the serotonin (5-hydroxytryptamine; 5-HT) metabolic pathway and for the incorporation of Trp into proteins, and α-[14C]methyl-L-tryptophan (α-MTrp) were measured. Measurements were done in rats treated with either saline or probenecid (200 mg/kg). In addn., the blood-brain barrier (BBB) permeability surface area products for Trp (PST) and α-MTrp (PSα) were measured in normal rats. The results suggest that, in both groups of rats, there is a highly significant correlation (Pearson Product Moment Correlation (PPMC)) between the brain uptake and trapping consts. for α-MTrp and those of Trp via the 5-HT metabolic pathway, but there is no significant correlation (PPMC) between either of these consts. and the PS products of either compd. There is also no significant correlation (PPMC) between the const. for the Trp incorporation into proteins with any of the other parameters. For all parameters, except Trp incorporation into proteins (α-MTrp is not incorporated into proteins), there was a highly significant correlation between the quantities measured for Trp and α-MTrp. The data presented here strongly suggests that the brain uptake and trapping of α-MTrp relates to brain 5-HT synthesis, and does not relate to the BBB transport or protein incorporation of Trp. On the basis of these results, as well as those previously reported, the authors concluded that trapping (unidirectional uptake) of α-MTrp can be converted to the 5-HT synthesis rates in the brain. From this also follows that labeled α-MTrp is a good tracer for in vivo evaluation of the brain 5-HT synthesis.
- 177Muzik, O.; Chugani, D. C.; Chakraborty, P.; Mangner, T.; Chugani, H. T. Analysis of [C-11]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivo. J. Cereb. Blood Flow Metab. 1997, 17, 659– 669, DOI: 10.1097/00004647-199706000-00007[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlsVGiurk%253D&md5=bca7d213d43039028a16eb43ea771cadAnalysis of [11C]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivoMuzik, Otto; Chugani, Diane C.; Chakraborty, Pulak; Mangner, Thomas; Chugani, Harry T.Journal of Cerebral Blood Flow and Metabolism (1997), 17 (6), 659-669CODEN: JCBMDN; ISSN:0271-678X. (Lippincott-Raven)The authors describe the tracer kinetic anal. of [C-11]-labeled alpha-methyl-tryptophan (AMT), an analog of tryptophan, which has been developed as a tracer for serotonin synthesis using positron emission tomog. (PET) in human brain. Dynamic PET data were acquired from young healthy volunteers as a series of 22 scans covering a total of 60 min and analyzed by a three-compartment, four-parameter model. In addn., functional images of the K-complex were created using the Patlak-plot approach. The application of a three-compartment model resulted in low identifiability of individual k-values, esp. that of k3. Model identifiability anal. using a singular value decompn. of the final sensitivity matrix showed parameter identifiability to increase by 50% when the Patlak-plot approach was used. K-complex values derived by the Patlak-plot approach overestimated the compartmental values by 10 to 20%, because of the violation of the dynamic equil. assumption. However, this bias was fairly const. in all structures of the brain. The rank order of K-complex values from different brain regions corresponded well to the regional concns. of serotonin in human brain. These results indicate that the Patlak-plot method can be readily applied to [C-11]AMT data to create functional images of the K-complex, reflecting serotonin synthesis rate, within an acceptable error margin.
- 178Chugani, D. C.; Chugani, H. T.; Muzik, O.; Shah, J. R.; Shah, A. K.; Canady, A.; Mangner, T. J.; Chakraborty, P. K. Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. Ann. Neurol. 1998, 44, 858– 866, DOI: 10.1002/ana.410440603[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M%252Fms1Omtg%253D%253D&md5=4d640553dbbb23d60b8f7f09002e3c68Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomographyChugani D C; Chugani H T; Muzik O; Shah J R; Shah A K; Canady A; Mangner T J; Chakraborty P KAnnals of neurology (1998), 44 (6), 858-66 ISSN:0364-5134.Several reports have indicated that cortical resection is effective in alleviating intractable epilepsy in children with tuberous sclerosis complex (TSC). Because of the multitude of cortical lesions, however, identifying the epileptogenic tuber(s) is difficult and often requires invasive intracranial electroencephalographic (EEG) monitoring. As increased concentrations of serotonin and serotonin-immunoreactive processes have been reported in resected human epileptic cortex, we used alpha-[11C]methyl-L-tryptophan ([11C]AMT) positron emission tomography (PET) to test the hypothesis that serotonin synthesis is increased interictally in epileptogenic tubers in patients with TSC. Nine children with TSC and epilepsy, aged 1 to 9 years (mean, 4 years 1 month), were studied. All children underwent scalp video-EEG monitoring, PET scans of glucose metabolism and serotonin synthesis, and EEG monitoring during both PET studies. [11C]AMT scans were coregistered with magnetic resonance imaging and with glucose metabolism scans. Whereas glucose metabolism PET showed multifocal cortical hypometabolism corresponding to the locations of tubers in all 9 children, [11C]AMT uptake was increased in one tuber (n=3), two tubers (n=3), three tubers (n=1), and four tubers (n=1) in 8 of the 9 children. All other tubers showed decreased [11C]AMT uptake. Ictal EEG data available in 8 children showed seizure onset corresponding to foci of increased [11C]AMT uptake in 4 children (including 2 with intracranial EEG recordings). In 2 children, ictal EEG was nonlocalizing, and in 1 child there was discordance between the region of increased [11C]AMT uptake and the region of ictal onset on EEG. The only child whose [11C]AMT scan showed no regions of increased uptake had a left frontal seizure focus on EEG; however, at the time of his [11C]AMT PET scan, his seizures had come under control. [11C]AMT PET may be a powerful tool in differentiating between epileptogenic and nonepileptogenic tubers in patients with TSC.
- 179Chugani, H. T.; Luat, A. F.; Kumar, A.; Govindan, R.; Pawlik, K.; Asano, E. α-[11C]-methyl-L-tryptophan-PET in 191 patients with tuberous sclerosis complex. Neurology 2013, 81, 674– 680, DOI: 10.1212/WNL.0b013e3182a08f3f[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1OqtLbO&md5=43c3ad9e55942d0536b222aa1df01dc4α-[11C]-Methyl-L-tryptophan-PET in 191 patients with tuberous sclerosis complexChugani, Harry T.; Luat, Aimee F.; Kumar, Ajay; Govindan, Rajkumar; Pawlik, Kathy; Asano, EishiNeurology (2013), 81 (7), 674-680CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objectives: This was an observational study done on a large cohort of patients with tuberous sclerosis complex (TSC) to det. whether (i) the presence of α-[C]-methyl-L-tryptophan (AMT) hotspots is related to the duration of seizure intractability, (ii) the presence of AMT hotspots is related to specific TSC gene mutations, and (iii) there is concordance between areas with an AMT hotspot and seizure lateralization/localization on scalp EEG. Methods: One hundred ninety-one patients (mean age: 6.7 years; median: 5 years; range: 3 mo to 37 years) with TSC and intractable epilepsy were included. All patients underwent AMT-PET scan. AMT uptake in each tuber and normal-appearing cortex was measured and correlated with clin., scalp EEG, and, if available, electrocorticog. data. Results: The longer the duration of seizure intractability, the greater the no. of AMT hotspots (r = 0.2; p = 0.03). AMT hotspots were seen in both TSC1 and TSC2. There was excellent agreement in seizure focus lateralization between ictal scalp EEG and AMT-PET (Cohen κ 0.94) in 68 of 95 patients in whom both ictal video-EEG and AMT-PET showed lateralizing findings; in 28 of 68 patients (41%), AMT was more localizing. Furthermore, AMT-PET was localizing in 10 of 17 patients (58%) with nonlateralized ictal EEG. Conclusion: AMT-PET, when used together with video-EEG, provides addnl. lateralization/localization data, regardless of TSC mutation. The duration of seizure intractability may predict the multiplicity of areas with AMT hotspots.
- 180Juhasz, C.; Chugani, D. C.; Muzik, O.; Shah, A.; Asano, E.; Mangner, T. J.; Chakraborty, P. K.; Sood, S.; Chugani, H. T. Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 2003, 60, 960– 968, DOI: 10.1212/01.WNL.0000049468.05050.F2[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7ktVKqsA%253D%253D&md5=95568b7095b1b1c8ec5c934a67f7fbadAlpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsyJuhasz C; Chugani D C; Muzik O; Shah A; Asano E; Mangner T J; Chakraborty P K; Sood S; Chugani H TNeurology (2003), 60 (6), 960-8 ISSN:.BACKGROUND: In children with tuberous sclerosis, the PET tracer alpha[11C]methyl-L-tryptophan (AMT) has been shown to be selectively taken up by epileptogenic tubers, thus allowing differentiation from nonepileptogenic tubers in the interictal state. OBJECTIVE: To determine whether cortical areas showing increased AMT uptake in children without tuberous sclerosis complex with intractable neocortical epilepsy indicate the epileptogenic zone, and to assess the relative contributions of AMT and 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET abnormalities to the localization of epileptogenic cortical regions. METHODS: Areas of increased AMT and decreased FDG uptake were marked objectively as regions with abnormal asymmetry using an in-house written software in 27 children who underwent comprehensive evaluation for resective epilepsy surgery. The marked PET abnormalities were compared to the locations of scalp and subdural EEG epileptiform abnormalities, as well as histology and surgical outcome. RESULTS: Focal cortical increases of AMT uptake were found in 15 patients. The lobar sensitivity (39.0%) of AMT PET for seizure onset was lower, but its specificity (100%) was higher (p < 0.0001) than that of hypometabolism on FDG PET (sensitivity 73.2%, specificity 62.7%). AMT PET abnormalities were smaller than corresponding FDG PET hypometabolic regions (p = 0.002), and increased AMT uptake occurred in two patients with nonlocalizing FDG PET. Histologically verified cortical developmental malformations were associated with increased AMT uptake (p = 0.044). Subdural electrodes adjacent to the area of increased AMT uptake were most often involved in seizure onset. CONCLUSIONS: Focal increase of cortical AMT uptake in children is less sensitive but more specific for the lobe of seizure onset than corresponding FDG PET hypometabolism, and it is often associated with epileptogenic cortical developmental malformations. AMT PET can assist placement of subdural electrodes even when MRI and FDG PET fail to provide adequate localizing information. Cortical areas adjacent to increased AMT uptake should be carefully addressed by intracranial EEG because these regions often show a high degree of epileptogenicity.
- 181Juhasz, C.; Chugani, D. C.; Padhye, U. N.; Muzik, O.; Shah, A.; Asano, E.; Mangner, T. J.; Chakraborty, P. K.; Sood, S.; Chugani, H. T. Evaluation with alpha-[11C]methyl-l-tryptophan positron emission tomography for reoperation after failed epilepsy surgery. Epilepsia 2004, 45, 124– 130, DOI: 10.1111/j.0013-9580.2004.30303.x[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c%252FjvFCjtQ%253D%253D&md5=f04dcbbec356603b71bbd94fcd4b723cEvaluation with alpha-[11C]methyl-L-tryptophan positron emission tomography for reoperation after failed epilepsy surgeryJuhasz Csaba; Chugani Diane C; Padhye Uma N; Muzik Otto; Shah Aashit; Asano Eishi; Mangner Tom J; Chakraborty Pulak K; Sood Sandeep; Chugani Harry TEpilepsia (2004), 45 (2), 124-30 ISSN:0013-9580.PURPOSE: Reoperation after failed cortical resection can alleviate seizures in patients with intractable neocortical epilepsy, provided that previously nonresected epileptic regions are accurately defined and removed. Most imaging modalities have limited value in identifying such regions after a previous surgery. Positron emission tomography (PET) using alpha-[11C]methyl-L-tryptophan (AMT) can detect epileptogenic cortical areas as regions with increased tracer uptake. This study analyzed whether increased cortical AMT uptake can detect nonresected epileptic foci in patients with previously failed neocortical resection. METHODS: Thirty-three young patients (age 3-26 years; mean age, 10.8 years) with intractable epilepsy of neocortical origin, and a previously failed cortical resection performed at various epilepsy centers, underwent further presurgical evaluation for reoperation. AMT-PET scans were performed 6 days to 7 years after the first surgery. Focal cortical areas with increased AMT uptake were objectively identified and correlated to ictal EEG data as well as clinical variables (age, postsurgical time, etiology). RESULTS: Cortical increases of AMT uptake were detected on the side of the previous resections in 12 cases. In two patients scanned shortly (within a week) after surgery, diffuse hemispheric increases were observed, without any further localization value. In contrast, in 10 (43%) of 23 patients scanned >2 months but within 2.3 years after surgery, focal cortical increases occurred, concordant with seizure onset on ictal EEG. Age, etiology (lesional vs. cryptogenic), epileptiform EEG activity during PET, or time of the last seizure were not significantly related to the presence of increased AMT uptake. All patients with localizing AMT-PET, who underwent reoperation, became seizure free (n = 5) or showed considerable improvement of seizure frequency (n = 2). CONCLUSIONS: AMT-PET can identify nonresected epileptic cortex in patients with a previously failed neocortical epilepsy surgery and, with proper timing for the scan, can assist in planning reoperation.
- 182Chen, Y.; Guillemin, G. J. Kynurenine pathway metabolites in humans: Disease and healthy states. Int. J. Tryptophan Res. 2009, 2, IJTR.S2097, DOI: 10.4137/IJTR.S2097
- 183Uyttenhove, C.; Pilotte, L.; Théate, I.; Stroobant, V.; Colau, D.; Parmentier, N.; Boon, T.; Van den Eynde, B. J. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 2003, 9, 1269– 1274, DOI: 10.1038/nm934[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXns1Clu7c%253D&md5=c2be3620862064fb40da547f976ccf95Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenaseUyttenhove, Catherine; Pilotte, Luc; Theate, Ivan; Stroobant, Vincent; Colau, Didier; Parmentier, Nicolas; Boon, Thierry; Van den Eynde, Benoit J.Nature Medicine (New York, NY, United States) (2003), 9 (10), 1269-1274CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)T lymphocytes undergo proliferation arrest when exposed to tryptophan shortage, which can be provoked by indoleamine 2,3-dioxygenase (IDO), an enzyme that is expressed in placenta and catalyzes tryptophan degrdn. Here we show that most human tumors constitutively express IDO. We also obsd. that expression of IDO by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.
- 184Juhász, C.; Dwivedi, S.; Kamson, D. O.; Michelhaugh, S. K.; Mittal, S. Comparison of amino acid positron emission tomographic radiotracers for molecular imaging of primary and metastatic brain tumors. Mol. Imaging 2014, 13, 7290.2014.00015, DOI: 10.2310/7290.2014.00015
- 185Alkonyi, B.; Barger, G. R.; Mittal, S.; Muzik, O.; Chugani, D. C.; Bahl, G.; Robinette, N. L.; Kupsky, W. J.; Chakraborty, P. K.; Juhasz, C. Accurate differentiation of recurrent gliomas from radiation injury by kinetic analysis of −11C-methyl-L-tryptophan PET. J. Nucl. Med. 2012, 53, 1058– 1064, DOI: 10.2967/jnumed.111.097881[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1ajtrvI&md5=d10cd5f37876861f8a84af5d9f48c521Accurate differentiation of recurrent gliomas from radiation injury by kinetic analysis of α-11C-methyl-L-tryptophan PETAlkonyi, Balint; Barger, Geoffrey R.; Mittal, Sandeep; Muzik, Otto; Chugani, Diane C.; Bahl, Gautam; Robinette, Natasha L.; Kupsky, William J.; Chakraborty, Pulak K.; Juhasz, CsabaJournal of Nuclear Medicine (2012), 53 (7), 1058-1064CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)PET of amino acid transport and metab. may be more accurate than conventional neuroimaging in differentiating recurrent gliomas from radiation-induced tissue changes. α-11C-methyl-L-tryptophan (11C-AMT) is an amino acid PET tracer that is not incorporated into proteins but accumulates in gliomas, mainly because of tumoral transport and metab. via the immunomodulatory kynurenine pathway. The aim of this study was to evaluate the usefulness of 11C-AMT PET supplemented by tracer kinetic anal. for distinguishing recurrent gliomas from radiation injury. Methods: Twenty-two 11C-AMT PET scans were obtained in adult patients who presented with a lesion suggestive of tumor recurrence on conventional MR11-6 y (mean, 3 y) after resection and postsurgical radiation of a World Health Organization grade II-IV glioma. Lesional standardized uptake values were calcd., as well as lesion-to-contralateral cortex ratios and 2 kinetic 11C-AMT PET parameters (vol. of distribution [VD], characterizing tracer transport, and unidirectional uptake rate [K]). Tumor was differentiated from radiation-injured tissue by histopathol. (n = 13) or 1-y clin. and MRI follow-up (n = 9). Accuracy of tumor detection by PET variables was assessed by receiver-operating-characteristic anal. Results: All 11C-AMT PET parameters were higher in tumors (n = 12) than in radiation injury (n = 10) (P ≤ 0.012 in all comparisons). The lesion-to-cortex K-ratio most accurately identified tumor recurrence, with highly significant differences both in the whole group (P < 0.0001) and in lesions with histol. verification (P = 0.006); the area under the receiver-operating-characteristic curve was 0.99. A lesion-to-cortex K-ratio threshold of 1.39 (i.e., a 39% increase) correctly differentiated tumors from radiation injury in all but 1 case (100% sensitivity and 91% specificity). In tumors that were high-grade initially (n = 15), a higher lesion-to-cortex K-ratio threshold completely sepd. recurrent tumors (all K-ratios ≥ 1.70) from radiation injury (all K-ratios < 1.50) (100% sensitivity and specificity). Conclusion: Kinetic anal. of dynamic 11C-AMT PET images may accurately differentiate between recurrent World Health Organization grade II-IV infiltrating gliomas and radiation injury. Sepn. of unidirectional uptake rates from transport can enhance the differentiating accuracy of 11C-AMT PET. Applying the same approach to other amino acid PET tracers might also improve their ability to differentiate recurrent gliomas from radiation injury.
- 186Miettinen, H.; Kononen, J.; Haapasalo, H.; Helén, P.; Sallinen, P.; Harjuntausta, T.; Helin, H.; Alho, H. Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: Relationship to cell proliferation. Cancer Res. 1995, 55, 2691– 2695[PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmtlWrt7Y%253D&md5=86e765d3b788beced8ed2207ea54c977Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferationMiettinen, Helena; Kononen, Juha; Haapasalo, Hannu; Hel´en, Pauli; Sallinen, Pauli; Harjuntausta, Tero; Helin, Heikki; Alho, HannuCancer Research (1995), 55 (12), 2691-5CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The expression of peripheral-type benzodiazepine receptor (PBR) and diazepam binding inhibitor (DBI) were studied in human astrocytic tumors using immunocytochem. and in situ hybridization. Both PBR and DBI were prominently expressed in neoplastic cells, whereas in normal brain their amt. was low or undetectable. Immunocytochem. double straining demonstrated that PBR and DBI were present in the same cells, suggesting the DBI may act in an autocrine manner in these cells. Anal. of 86 cases showed that PBR expression was statistically significantly assocd. with tumor malignancy grade (P = 0.004) and the proliferative index as detd. by immunocytochem. with the MIB-1 antibody (P = 0.004). Patients having tumors with high levels of PBR-immunoreactive cells had a shorter life expectancy than patients whose tumors showed lower PBR contents (P = 0.024). In conclusion, these results show that PBR expression is higher in neoplastic cells than in normal brain tissue. They also suggest that PBR immunocytochem. might be useful in evaluating malignancy in brain tumors.
- 187Vlodavsky, E.; Soustiel, J. F. Immunohistochemical expression of peripheral benzodiazepine receptors in human astrocytomas and its correlation with grade of malignancy, proliferation, apoptosis and survival. J. Neuro-Oncol. 2006, 81, 1– 7, DOI: 10.1007/s11060-006-9199-9
- 188Su, Z.; Roncaroli, F.; Durrenberger, P. F.; Coope, D. J.; Karabatsou, K.; Hinz, R.; Thompson, G.; Turkheimer, F. E.; Janczar, K.; Du Plessis, D.; Brodbelt, A.; Jackson, A.; Gerhard, A.; Herholz, K. The 18-kDa mitochondrial translocator protein in human gliomas: An 11C-(R)PK11195 PET imaging and neuropathology study. J. Nucl. Med. 2015, 56, 512– 517, DOI: 10.2967/jnumed.114.151621[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmvVWmtLg%253D&md5=0eab0b842853bbdf86eb0f2275058d3fThe 18-kDa mitochondrial translocator protein in human gliomas: an 11C-(R)PK11195 PET imaging and neuropathology studySu, Zhangjie; Roncaroli, Federico; Durrenberger, Pascal F.; Coope, David J.; Karabatsou, Konstantina; Hinz, Rainer; Thompson, Gerard; Turkheimer, Federico E.; Janczar, Karolina; Du Plessis, Daniel; Brodbelt, Andrew; Jackson, Alan; Gerhard, Alexander; Herholz, KarlJournal of Nuclear Medicine (2015), 56 (4), 512-517CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)The 18-kDa mitochondrial translocator protein (TSPO) is upregulated in high-grade astrocytomas and can be imaged by PET using the selective radiotracer 11C-(R)PK11195. We investigated 11C-(R)PK11195 binding in human gliomas and its relationship with TSPO expression in tumor tissue and glioma-assocd. microglia/macrophages (GAMs) within the tumors. Methods: Twenty-two glioma patients underwent dynamic 11C-(R)PK11195 PET scans and perfusion MR imaging acquisition. Parametric maps of 11C-(R)PK11195 binding potential (BPND) were generated. Co-registered MR/PET images were used to guide tumor biopsy. The tumor tissue was quant. assessed for TSPO expression and infiltration of GAMs using immunohistochem. and double immunofluorescence. The imaging and histopathol. parameters were compared among different histotypes and grades and correlated with each other. Results: BPND of 11C-(R)PK11195 in high-grade gliomas was significantly higher than in low-grade astrocytomas and low-grade oligodendrogliomas. TSPO in gliomas was expressed predominantly by neoplastic cells, and its expression correlated pos. with BPND in the tumors. GAMs only partially contributed to the overall TSPO expression within the tumors, and TSPO expression in GAMs did not correlate with tumor BPND. Conclusion: PET with 11C-(R)PK11195 in human gliomas predominantly reflects TSPO expression in tumor cells. It therefore has the potential to effectively stratify patients who are suitable for TSPO-targeted treatment.
- 189Junck, L.; Olson, J. M. M.; Ciliax, B. J.; Koeppe, R. A.; Watkins, G. L.; Jewett, D. M.; McKeever, P. E.; Wieland, D. M.; Kilbourn, M. R.; Starosta-Rubinstein, S.; Mancini, W. R.; Kuhl, D. E.; Greenberg, H. S.; Young, A. B. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann. Neurol. 1989, 26, 752– 758, DOI: 10.1002/ana.410260611[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhtFCqtbk%253D&md5=b9546f8a15368e8381576cdc3f5aabfaPET imaging of human gliomas with ligands for the peripheral benzodiazepine binding siteJunck, Larry; Olson, James M. M.; Ciliax, Brian J.; Koeppe, Robert A.; Watkins, G. Leonard; Jewett, Douglas M.; McKeever, Paul E.; Wieland, Donald M.; Kilbourn, Michael R.; et al.Annals of Neurology (1989), 26 (6), 752-8CODEN: ANNED3; ISSN:0364-5134.Human gliomas were imaged in vivo using ligands for the peripheral-type benzodiazepine binding site (or ω3 binding site) and positron emission tomog. (PET). Although gliomas have a high d. of the peripheral-type benzodiazepine binding site, PET scans with a selective ligand for this site, [11C]Ro5-4864, failed to demonstrate higher radioactivity levels in human gliomas than in brain. In vitro studies of surgically removed specimens of human glioma demonstrated little binding of Ro5-4864 but high levels of binding of another selective ligand, PK 11195. Scans with [11C]PK 11195 demonstrated increased radioactivity in glioma compared to brain in 8 of 10 patients. Radioactivity in tumor and the ratios of radioactivity in tumor to that in remote gray and in white matter correlated significantly with the specific activity of [11C]PK 11195, suggesting that accumulation represents saturable high-affinity binding. Thus, PK 11195 manifests greater binding than Ro5-4864 to the peripheral-type benzodiazepine binding site on human gliomas, and human gliomas can be successfully imaged using [11C]PK 11195 and PET.
- 190Pappata, S.; Cornu, P.; Samson, Y.; Prenant, C.; Benavides, J.; Scatton, B.; Crouzel, C.; Hauw, J. J.; Syrota, A. PET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: A case report. J. Nucl. Med. 1991, 32, 1608– 1610[PubMed], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3Mzjt1Oitw%253D%253D&md5=cd014a471a37f2b8a7153960231aa36aPET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: a case reportPappata S; Cornu P; Samson Y; Prenant C; Benavides J; Scatton B; Crouzel C; Hauw J J; Syrota AJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1991), 32 (8), 1608-10 ISSN:0161-5505.The utility of the peripheral type benzodiazepine site ligand 11C-PK 11195, for imaging human glioma in conjunction with Positron Emission Tomography, relies on a high specific binding of the tracer to tumoral peripheral type benzodiazepines sites. In a patient with glioblastoma, we found that 11C-PK 11195 binding was two-fold higher in the tumor than in normal gray matter and that 30% of tumoral binding could be displaced by a large excess of unlabeled drug. These findings suggest that tumoral retention of the ligand is due, in part, to specific binding.
- 191Roncaroli, F.; Su, Z.; Herholz, K.; Gerhard, A.; Turkheimer, F. E. TSPO expression in brain tumours: Is TSPO a target for brain tumour imaging?. Clin Transl Imaging. 2016, 4, 145– 156, DOI: 10.1007/s40336-016-0168-9[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FhtFKhtA%253D%253D&md5=c5766dd4a5305f8db0633cd58b0d1142TSPO expression in brain tumours: is TSPO a target for brain tumour imaging?Roncaroli Federico; Su Zhangjie; Herholz Karl; Gerhard Alexander; Turkheimer Federico EClinical and translational imaging (2016), 4 (), 145-156 ISSN:2281-5872.Positron emission tomography (PET) alone or in combination with MRI is increasingly assuming a central role in the development of diagnostic and therapeutic strategies for brain tumours with the aim of addressing tumour heterogeneity, assisting in patient stratification, and contributing to predicting treatment response. The 18 kDa translocator protein (TSPO) is expressed in high-grade gliomas, while its expression is comparatively low in normal brain. In addition, the evidence of elevated TSPO in neoplastic cells has led to studies investigating TSPO as a transporter of anticancer drugs for brain delivery and a selective target for tumour tissue. The TSPO therefore represents an ideal candidate for molecular imaging studies. Knowledge of the biology of TSPO in normal brain cells, in-depth understanding of TSPO functions and biodistribution in neoplastic cells, accurate methods for quantification of uptake of TSPO tracers and pharmacokinetic data regarding TSPO-targeted drugs are required before introducing TSPO PET and TSPO-targeted treatment in clinical practice. In this review, we will discuss the impact of preclinical PET studies and the application of TSPO imaging in human brain tumours, the advantages and disadvantages of TSPO imaging compared to other imaging modalities and other PET tracers, and pathology studies on the extent and distribution of TSPO in gliomas. The suitability of TSPO as molecular target for treatment of brain tumours will also be the appraised.
- 192Su, Z.; Herholz, K.; Gerhard, A.; Roncaroli, F.; Du Plessis, D.; Jackson, A.; Turkheimer, F.; Hinz, R. [11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 1406– 1419, DOI: 10.1007/s00259-013-2447-2[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1GmtbjK&md5=1ef1a7fa51991575e9d79e30113a83e8[11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approachesSu, Zhangjie; Herholz, Karl; Gerhard, Alexander; Roncaroli, Federico; Du Plessis, Daniel; Jackson, Alan; Turkheimer, Federico; Hinz, RainerEuropean Journal of Nuclear Medicine and Molecular Imaging (2013), 40 (9), 1406-1419CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: Translocator protein (TSPO) is a biomarker of neuroinflammation that can be imaged by PET using [11C]-(R)PK11195. We sought to characterize the [11C]-(R)PK11195 kinetics in gliomas of different histotypes and grades, and to compare two ref. tissue input functions (supervised cluster anal. vs. cerebellar gray matter) for the estn. of [11C]-(R)PK11195 binding in gliomas and surrounding brain structures. Methods: Twenty-three glioma patients and ten age-matched controls underwent structural MRI and dynamic [11C]-(R)PK11195 PET scans. Tissue time-activity curves (TACs) were extd. from tumor regions as well as gray matter (GM) and white matter (WM) of the brains. Parametric maps of binding potential (BPND) were generated with the simplified ref. tissue model using the two input functions, and were compared with each other. TSPO expression was assessed in tumor tissue sections by immunohistochem. Results: Three types of regional kinetics were obsd. in individual tumor TACs: GM-like kinetics (n = 6, clearance of the tracer similar to that in cerebellar GM), WM-like kinetics (n = 8, clearance of the tracer similar to that in cerebral WM) and a form of mixed kinetics (n = 9, intermediate rate of clearance). Such kinetic patterns differed between low-grade astrocytomas (WM-like kinetics) and oligodendrogliomas (GM-like and mixed kinetics), but were independent of tumor grade. There was good agreement between parametric maps of BPND derived from the two input functions in all controls and 10 of 23 glioma patients. In 13 of the 23 patients, BPND values derived from the supervised cluster input were systematically smaller than those using the cerebellar input. Immunohistochem. confirmed that TSPO expression increased with tumor grade. Conclusion: The three types of [11C]-(R)PK11195 kinetics in gliomas are detd. in part by tracer delivery, and indicated that kinetic anal. is a valuable tool in the study of gliomas with the potential for in vivo discrimination between low-grade astrocytomas and oligodendrogliomas. Supervised cluster and cerebellar input functions produced consistent BPND ests. in approx. half of the gliomas investigated, but had a systematic difference in the remainder. The cerebellar input is preferred based on theor. and practical considerations.
- 193Ashmore-Harris, C.; Iafrate, M.; Saleem, A.; Fruhwirth, G. O. Non-invasive reporter gene imaging of cell therapies, including T cells and stem cells. Mol. Ther. 2020, 28, 1392– 1416, DOI: 10.1016/j.ymthe.2020.03.016[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFSksLvN&md5=b28b160002f6de9ddf960f6e55a69a90Non-invasive Reporter Gene Imaging of Cell Therapies, including T Cells and Stem CellsAshmore-Harris, Candice; Iafrate, Madeleine; Saleem, Adeel; Fruhwirth, Gilbert O.Molecular Therapy (2020), 28 (6), 1392-1416CODEN: MTOHCK; ISSN:1525-0024. (Cell Press)Cell therapies represent a rapidly emerging class of new therapeutics. They are intended and developed for the treatment of some of the most prevalent human diseases, including cancer, diabetes, and for regenerative medicine. Currently, they are largely developed without precise assessment of their in vivo distribution, efficacy, or survival either clin. or preclinically. However, it would be highly beneficial for both preclin. cell therapy development and subsequent clin. use to assess these parameters in situ to enable enhancements in efficacy, applicability, and safety. Mol. imaging can be exploited to track cells non-invasively on the whole-body level and can enable monitoring for prolonged periods in a manner compatible with rapidly expanding cell types. In this review, we explain how in vivo imaging can aid the development and clin. translation of cell-based therapeutics. We describe the underlying principles governing non-invasive in vivo long-term cell tracking in the preclin. and clin. settings, including available imaging technologies, reporter genes, and imaging agents as well as pitfalls related to exptl. design. Our emphasis is on adoptively transferred T cell and stem cell therapies.
- 194Brader, P.; Serganova, I.; Blasberg, R. G. Noninvasive molecular imaging using reporter genes. J. Nucl. Med. 2013, 54, 167– 172, DOI: 10.2967/jnumed.111.099788[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlGks7g%253D&md5=247b4b1193ef6eb663a6fd40f45da5e2Noninvasive molecular imaging using reporter genesBrader, Peter; Serganova, Inna; Blasberg, Ronald G.Journal of Nuclear Medicine (2013), 54 (2), 167-172CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)A review. Noninvasive reporter gene imaging is a component of mol. imaging. Reporter imaging can provide noninvasive assessments of endogenous biol. processes in living subjects and can be performed using different imaging modalities. This review will focus on radionuclide-based reporter gene imaging as developed and applied in preclin. and clin. studies. Examples of different reporter systems are presented, with a focus on human reporter systems. Selected applications are discussed, including adoptive cell therapies, gene and oncoviral therapies, oncogenesis, signal pathway monitoring, and imaging drug treatment. Mol. imaging, and noninvasive reporter gene imaging in particular, are making important contributions to our understanding of disease development, progression, and treatment in our current era of mol. medicine and individualized patient care.
- 195Sellmyer, M. A.; Lee, I.; Hou, C.; Lieberman, B. P.; Zeng, C.; Mankoff, D. A.; Mach, R. H. Quantitative PET reporter gene imaging with [11C]trimethoprim. Mol. Ther. 2017, 25, 120– 126, DOI: 10.1016/j.ymthe.2016.10.018[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFCmtbo%253D&md5=9f42273c2b3a6c2b81dbc5028b66d1dcQuantitative PET Reporter Gene Imaging with [11C]TrimethoprimSellmyer, Mark A.; Lee, Iljung; Hou, Catherine; Lieberman, Brian P.; Zeng, Chenbo; Mankoff, David A.; Mach, Robert H.Molecular Therapy (2017), 25 (1), 120-126CODEN: MTOHCK; ISSN:1525-0024. (Cell Press)There is a need for improved methods to image genetically engineered cells, including immune cells used for cell-based therapy. Given the genetic manipulation inherent to gene therapy, the use of a reporter protein is a logical soln. and positron emission tomog. (PET) can provide the desired sensitivity and spatial localization. We developed a broadly applicable PET imaging strategy based on the small bacterial protein E. coli dihydrofolate reductase (Ec dhfr) and its highly specific small mol. inhibitor, trimethoprim (TMP). The difference in TMP affinity for bacterial compared to mammalian DHFR suggests that a TMP radioligand would have a low background in unmodified mammalian tissues and high retention in Ec dhfr engineered cells, providing high contrast imaging. Here, we describe the in vitro properties of [11C]TMP and show over 10-fold increased signal in transgenic Ec dhfr cells compared to control. In a mouse xenograft model, [11C]TMP rapidly accumulated in Ec dhfr carrying cells within minutes of i.v. administration. Moreover, [11C]TMP can identify less than a million xenografted cells in a small vol. in tissues other than the abdominal compartment. This limit of detection is a clin. relevant no. and bodes well for clin. translation esp. given that [11C]TMP is an isotopologue of clin. approved antibiotic.
- 196Grassi, I.; Nanni, C.; Allegri, V.; Morigi, J. J.; Montini, G. C.; Castellucci, P.; Fanti, S. The clinical use of PET with (11)C-acetate. Am. J. Nucl. Med. Mol. Imaging. 2012, 2, 33– 47[PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFOrtLY%253D&md5=2f1ef97bea8ca6c6b42b6c8d956b6398The clinical use of PET with 11C-acetateGrassi, Ilaria; Nanni, Cristina; Allegri, Vincenzo; Morigi, Joshua James; Montini, Gian Carlo; Castellucci, Paolo; Fanti, StefanoAmerican Journal of Nuclear Medicine and Molecular Imaging (2012), 2 (1), 33-47CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)The aim of this review is to evaluate clin. applications of 11C-acetate positron emission tomog. (PET). Acetate is quickly metabolized into acetyl-CoA in human cells. In this form it can either enter into the tricarboxylic acid cycle, thus producing energy, as happens in the myocardium, or participate in cell membrane lipid synthesis, as happens in tumor cells. 11C-acetate PET was originally employed in cardiol., to study myocardial oxygen metab. More recently it has also been used to evaluate myocardial perfusion, as well as in oncol. The first studies of 11C-acetate focused on its use in prostate cancer. Subsequently, 11C-acetate was studied in other urol. malignancies, as well as renal cell carcinoma and bladder cancer. Well differentiated hepatocellular carcinoma represents an 18F-fluoro-deoxyglucose (18F-FDG) PET pitfall, so many authors have proposed to use 11C-acetate in addn. to 18F-FDG in studying this tumor. 11C-acetate PET has also been used in other malignancies, such as brain tumors and lung carcinoma. Some authors reported a few cases in which 11C-acetate PET incidentally found multiple myeloma or rare tumors, such as thymoma, multicentric angiomyolipoma of the kidney and cerebellopontine angle schwannoma. Lastly, 11C-acetate PET was also employed in a differential diagnosis case between glioma and encephalitis. The numerous studies on 11C-acetate have demonstrated that it can be used in cardiol. and oncol. with no contraindications apart from pregnancy and the necessity of a rapid scan. Despite its limited availability, this tracer can surely be considered to be a promising one, because of its versatility and capacity to even detect non 18F-FDG-avid neoplasm, such as differentiated lung cancer or hepatocellular carcinoma.
- 197Brown, M.; Marshall, D. R.; Sobel, B. E.; Bergmann, S. R. Delineation of myocardial oxygen utilization with carbon-11-labeled acetate. Circulation 1987, 76, 687– 696, DOI: 10.1161/01.CIR.76.3.687[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2szgt1WlsA%253D%253D&md5=69acf224dbf5bdf7db867a49edf8e380Delineation of myocardial oxygen utilization with carbon-11-labeled acetateBrown M; Marshall D R; Sobel B E; Bergmann S RCirculation (1987), 76 (3), 687-96 ISSN:0009-7322.Although positron-emission tomography (PET) with labeled fatty acid delineates infarct size and permits qualitative assessment of fatty acid utilization, quantification of oxidative metabolism is limited by complex alterations in the pattern of utilization of fatty acid during ischemia and reperfusion. Because metabolism of acetate by myocardium is less complex than that of glucose or palmitate, we characterized kinetics of utilization of radiolabeled acetate in 37 isolated rabbit hearts perfused with modified Krebs-Henseleit buffer and performed a pilot tomographic study in man. Results of initial experiments with carbon-14-labeled acetate (14C-acetate) indicated that the steady-state extraction fraction of acetate averaged 61.5 +/- 4.0% in control hearts (n = 4), 93.6 +/- 0.9% in hearts rendered ischemic (n = 4), and 54.8 +/- 4.0% in hearts reperfused after 60 min of ischemia (n = 3). Oxidation of 14C-acetate, assessed from the rate of efflux of 14CO2 in the venous effluent, correlated closely with the rate of oxygen consumption under diverse metabolic conditions (r = .97, p less than .001). In addition, no significant differences were observed between rates of efflux of total 14C in all chemical species (reflecting total clearance of tracer from myocardium) and efflux of 14CO2. Clearance of 11C-acetate, measured externally with gamma probes in normal and ischemic myocardium, correlated closely with clearance of 14C-acetate measured directly in the effluent (r = .99, p less than .001) and with overall myocardial oxygen consumption (r = .95, p less than .001). Accumulation and clearance of 11C-acetate from human myocardium with PET demonstrated kinetics comparable to those seen with radiolabeled acetate in vitro. Thus externally detectable clearance of 11C-acetate provides a quantitative index of myocardial oxidative metabolism despite variation in the patterns of intermediary metabolism that confounds interpretation of results with conventionally used tracers such as glucose and fatty acid.
- 198Brown, M. A.; Myears, D. W.; Bergmann, S. R. Validity of estimates of myocardial oxidative metabolism with carbon-11 acetate and positron emission tomography despite altered patterns of substrate utilization. J. Nucl. Med. 1989, 30, 187– 193[PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M3ptlansA%253D%253D&md5=e9d95f6004f07a01565ba16a2223debbValidity of estimates of myocardial oxidative metabolism with carbon-11 acetate and positron emission tomography despite altered patterns of substrate utilizationBrown M A; Myears D W; Bergmann S RJournal of nuclear medicine : official publication, Society of Nuclear Medicine (1989), 30 (2), 187-93 ISSN:0161-5505.We recently demonstrated that the myocardial turnover rate constant (k) measured noninvasively with positron emission tomography (PET) after intravenous administration of [11C]acetate provides a reliable index of myocardial oxidative metabolism (MVO2) theoretically independent of the pattern of myocardial substrate use. However, because estimates of metabolism with other metabolic tracers are sensitive to substrate use, we measured k in 12 dogs during baseline conditions and again after infusion of either glucose (n = 8) or Intralipid (n = 4), interventions that raised arterial glucose or fatty acids by more than fivefold with concomitant changes in myocardial substrate use. Following glucose administration k increased, but no difference was detected after compensation for changes in hemodynamics and myocardial work induced by the infusion (0.18 +/- 0.03 min-1 (t1/2 = 3.9 min) at baseline compared with 0.22 +/- 0.06 min-1 (t1/2 = 3.2 min, p = N.S.). k was not affected by Intralipid infusion (k = 0.15 +/- 0.06 min-1 at baseline and 0.14 +/- 0.04 min-1 during infusion), and correlated closely with MVO2 measured directly (n = 19 comparisons, r = 0.89). The results indicate that estimates of MVO2 using [11C]acetate and PET are valid despite changes in the pattern of myocardial substrate utilization.
- 199Beanlands, R. S.; Schwaiger, M. Changes in myocardial oxygen consumption and efficiency with heart failure therapy measured by 11C acetate PET. Can. J. Cardiol. 1995, 11, 293– 300[PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2M3ksF2jtQ%253D%253D&md5=81b20d1466f64677e4e5af5a422ff742Changes in myocardial oxygen consumption and efficiency with heart failure therapy measured by 11C acetate PETBeanlands R S; Schwaiger MThe Canadian journal of cardiology (1995), 11 (4), 293-300 ISSN:0828-282X.The application of 11C acetate kinetics determined by positron emission tomography (PET) imaging has been proposed as a noninvasive means to measure myocardial oxygen consumption in order to determine myocardial efficiency. Such an approach considers the balance of the effect of ventricular performance and myocardial oxygen consumption (MVO2), which may be important in the assessment of heart failure but is not usually evaluated by current methods. In this paper, the authors review their previously published series of studies, in which the aim was to: first, apply the 11C acetate PET approach in patients with dilated cardiomyopathy in order to determine myocardial oxidative metabolism and estimate myocardial efficiency; second, verify a correlation between 11C acetate kinetics and directly measured MVO2; and third, evaluate the effects of dobutamine and nitroprusside on MVO2 and efficiency in dilated cardiomyopathy. In these previous studies, 13 patients with severe dilated cardiomyopathy were studied, via echocardiography, hemodynamic and PET studies, at baseline and during drug infusion. Seven patients were given dobutamine and six were given nitroprusside. A two-compartment kinetic model approach was applied to 11C time activity curves obtained from dynamic 11C acetate PET imaging to determine the clearance rate constant, k2. Myocardial efficiency was estimated from a work metabolic index, defined as (stroke work index multiplied by heart rate) divided by k2. The k2 significantly increased with dobutamine (P < or = 0.05), consistent with increased MVO2, and tended to decrease with nitroprusside. The work metabolic index derived from hemodynamic parameters increased significantly with both drug regimens (P < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
- 200Kudo, T. Metabolic imaging using PET. Eur. J. Nucl. Med. Mol. Imaging 2007, 34 (S1), 49– 61, DOI: 10.1007/s00259-007-0440-3[Crossref], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVGgs7c%253D&md5=6226907f0de9d6c580d4488c32e185bbMetabolic imaging using PETKudo, TakashiEuropean Journal of Nuclear Medicine and Molecular Imaging (2007), 34 (Suppl. 1), S49-S61CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. Introduction: There is growing evidence that myocardial metab. plays a key role not only in ischemic heart disease but also in a variety of diseases which involve myocardium globally, such as heart failure and diabetes mellitus. Understanding myocardial metab. in such diseases helps to elucidate the pathophysiol. and assists in making therapeutic decisions. Measurement: As well as providing information on regional changes, PET can deliver quant. information about both regional and global changes in metab. This capability of quant. measurement is one of the major advantages of PEt along with physiol. positron tracers, esp. relevant in evaluating diseases which involve the whole myocardium. Discussion: This review discusses major PET tracers for metabolic imaging and their clin. applications and contributions to research regarding ischemic heart disease and other diseases such as heart failure and diabetic heart disease. Future applications of positron metabolic tracers of the detection of vulnerable plaque are also highlighted briefly.
- 201Timmer, S. A. J.; Lubberink, M.; Germans, T.; Götte, M. J. W.; ten Berg, J. M.; ten Cate, F. J.; van Rossum, A. C.; Lammertsma, A. A.; Knaapen, P. Potential of [11C]acetate for measuring myocardial blood flow: Studies in normal subjects and patients with hypertrophic cardiomyopathy. J. Nucl. Cardiol. 2010, 17, 264– 275, DOI: 10.1007/s12350-009-9181-y[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c7ps1Kitg%253D%253D&md5=ed07a56a423db5ceb909e682b520671dPotential of [11C]acetate for measuring myocardial blood flow: Studies in normal subjects and patients with hypertrophic cardiomyopathyTimmer S A J; Lubberink M; Germans T; Gotte M J W; ten Berg J M; ten Cate F J; van Rossum A C; Lammertsma A A; Knaapen PJournal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology (2010), 17 (2), 264-75 ISSN:.BACKGROUND: Measuring the rate of clearance of carbon-11 labelled acetate from myocardium using positron emission tomography (PET) is an accepted technique for noninvasively assessing myocardial oxygen consumption. Initial myocardial uptake of [(11)C]acetate, however, is related to myocardial blood flow (MBF) and several tracer kinetic models for quantifying MBF using [(11)C]acetate have been proposed. The objective of this study was to assess these models. METHODS: Eighteen healthy subjects and 18 patients with hypertrophic cardiomyopathy (HCM) were studied under baseline conditions with [(11)C]acetate and [(15)O]water. Four previously reported methods, including single- and multi-tissue compartment models, were used to calculate MBF from the measured [(11)C]acetate rate of influx K (1) and the (previously) reported relationship between K (1) and MBF. These MBF values were then compared with those derived from corresponding [(15)O]water studies. RESULTS: For all models, correlations between [(11)C]acetate and [(15)O]water-derived MBF ranged from .67 to .86 (all P < .005) in the control group and from .73 to .85 (all P < .001) in the HCM group. Two out of four models systematically underestimated perfusion with [(11)C]acetate, whilst the third model resulted in an overestimation. The fourth model, based on a simple single tissue compartment model with spillover, partial volume and recirculating metabolite corrections, resulted in a regression equation with a slope of near unity and an Y-intercept of almost zero (controls, K(1) = .74[MBF] + .09, r = .86, SEE = .13, P < .001 and HCM, K(1) = .89[MBF] + .03, r = .85, SEE = .12, P < .001). CONCLUSION: [(11)C]acetate enables quantification of MBF in fairly good agreement with actual MBF in both healthy individuals and patients with HCM. A single tissue compartment model with standardized correction for recirculating metabolites and with corrections for partial volume and spillover provided the best results.
- 202Schindler, T. H.; Marashdeh, W.; Solnes, L. Clinical application of myocardial blood flow quantification in CAD patients. Annals of Nuclear Cardiology. 2016, 2, 84– 93, DOI: 10.17996/ANC.02.01.84
- 203Manabe, O.; Naya, M.; Tamaki, N. Feasibility of PET for the management of coronary artery disease: Comparison between CFR and FFR. J. Cardiol. 2017, 70, 135– 140, DOI: 10.1016/j.jjcc.2017.03.002[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czoslCjsQ%253D%253D&md5=966e93a64a977da4aa1da1d49ec259b9Feasibility of PET for the management of coronary artery disease: Comparison between CFR and FFRManabe Osamu; Tamaki Nagara; Naya MasanaoJournal of cardiology (2017), 70 (2), 135-140 ISSN:.Myocardial perfusion imaging using positron emission tomography (PET) allows both qualitative and quantitative measurement. The quantitative myocardial blood flow and coronary flow reserve (CFR) are reliable indices for evaluating functional severity, influenced by both epicardial stenosis and microvascular disease. Fractional flow reserve (FFR) also reflects physiological stenosis, which measures the pressure differences across a coronary artery stenosis during maximum hyperemia. Discordance between CFR and FFR has been noticed in estimating the functional significance of coronary stenosis. In this review, we summarize the feasibility of PET for the management of coronary artery disease compared to FFR.
- 204Stanley, W. C.; Recchia, F. A.; Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 2005, 85, 1093– 1129, DOI: 10.1152/physrev.00006.2004[Crossref], [PubMed], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsFylsr0%253D&md5=90ec99df2f81386d632f74490be7ad04Myocardial substrate metabolism in the normal and failing heartStanley, William C.; Recchia, Fabio A.; Lopaschuk, Gary D.Physiological Reviews (2005), 85 (3), 1093-1129CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review. The alterations in myocardial energy substrate metab. that occur in heart failure, and the causes and consequences of these abnormalities, are poorly understood. There is evidence to suggest that impaired substrate metab. contributes to contractile dysfunction and to the progressive left ventricular remodeling that are characteristic of the heart failure state. The general concept that has recently emerged is that myocardial substrate selection is relatively normal during the early stages of heart failure; however, in the advanced stages there is a downregulation in fatty acid oxidn., increased glycolysis and glucose oxidn., reduced respiratory chain activity, and an impaired reserve for mitochondrial oxidative flux. This review discusses 1) the metabolic changes that occur in chronic heart failure, with emphasis on the mechanisms that regulate the changes in the expression of metabolic genes and the function of metabolic pathways; 2) the consequences of these metabolic changes on cardiac function; 3) the role of changes in myocardial substrate metab. on ventricular remodeling and disease progression; and 4) the therapeutic potential of acute and long-term manipulation of cardiac substrate metab. in heart failure.
- 205Bergmann, S. Imaging of myocardial fatty acid metabolism with PET. Journal of Nuclear Cardiology. 2007, 14, S118– S124, DOI: 10.1016/j.nuclcard.2007.02.007
- 206Bielefeld, D.; Vary, T.; Neely, J. Inhibition of carnitine palmitoyl-CoA transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscle. J. Mol. Cell. Cardiol. 1985, 17, 619– 625, DOI: 10.1016/S0022-2828(85)80030-4[Crossref], [PubMed], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXltVamtLo%253D&md5=1e2e66720da649341a4e22a39e377aedInhibition of carnitine palmitoyl-CoA transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscleBielefeld, David R.; Vary, Thomas C.; Neely, James R.Journal of Molecular and Cellular Cardiology (1985), 17 (6), 619-25CODEN: JMCDAY; ISSN:0022-2828.High concns. of lactate and oxfenicine inhibit fatty acid oxidn. in cardiac muscle. The site of this inhibition was investigated in isolated perfused rat hearts. In hearts perfused with glucose (11 mM) and [U-14C]palmitate (1.0 mM), addn. of 5 mM lactate caused a 38% redn. in 14CO2 prodn. Tissue levels of long-chain acylcarnitine decreased, suggesting that inhibition occurred at either fatty acyl-CoA synthetase or carnitine acyl-CoA transferase. Cytosolic levels of acyl-CoA are low compared with mitochondrial levels and changes in acyl-CoA within the cytosolic compartment cannot be estd. directly. Consequently, the rate of conversion of [14C]palmitate to neutral lipids was used as an indicator of cytosolic acyl-CoA levels. Lactate caused a 100% increase in [14C]fatty acid conversion to triglycerides, suggesting that cytosolic levels of acyl-CoA increased in assocn. with decreased acylcarnitine. Thus, lactate inhibited fatty acid oxidn. at the level of carnitine acyl-CoA transferase. Oxfenicine (2 mM) reduced fatty acid oxidn. by 45%, decreased acylcarnitine levels by 80%, and increased conversion of [14C]palmitate to neutral lipids by 44%, suggesting that oxfenicine also inhibits fatty acid oxidn. at level of carnitine acyl-CoA transferase. Apparently, carnitine acyl-CoA transferase is an important site of control in the pathway of fatty acid oxidn.
- 207Bartels, G. L.; Remme, W. J.; Scholte, H. R. Acute myocardial ischaemia induces cardiac carnitine release in man. Eur. Heart J. 1997, 18, 84– 90, DOI: 10.1093/oxfordjournals.eurheartj.a015122[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3gtF2rtA%253D%253D&md5=59a2163193838ed91230f7d1df3f94deAcute myocardial ischaemia induces cardiac carnitine release in manBartels G L; Remme W J; Scholte H REuropean heart journal (1997), 18 (1), 84-90 ISSN:0195-668X.In animal studies, prolonged periods of ischaemia decrease the cardiac carnitine content. However, whether in humans the heart loses carnitine during short-term ischaemia, and whether this is related to ischaemia-induced cardiac dysfunction, is as yet unknown. Carnitine kinetics were investigated in 28 normotensive patients with significant left coronary artery disease, during and after incremental atrial pacing. To evaluate carnitine kinetics from the ischaemic area, patients were grouped as those with (n = 22) or without (n = 6) myocardial lactate production. Atrial pacing resulted in a comparable maximal heart rate and ST depression in both groups. Carnitine kinetics did not change in those without lactate production. In contrast, coronary venous free carnitine levels increased significantly by 9% during pacing in those with lactate production. Cardiac free carnitine balance changed from uptake (255 +/- 107 pmol.min-1, mean +/- SEM) to release, (-150 +/- 66 pmol.min-1) at 30 min after pacing in the group with lactate production. Arterial and coronary venous differences in free carnitine were significantly correlated with myocardial lactate extraction immediately after pacing. The change in coronary venous free carnitine was significantly correlated with the change in left ventricular ejection fraction at 10 min after pacing. Thus, in patients with coronary artery disease, short-term mild myocardial ischaemia results in significant cardiac free carnitine loss.
- 208Schön, H. R.; Schelbert, H. R.; Robinson, G.; Najafi, A.; Huang, S.-C.; Hansen, H.; Barrio, J.; Kuhl, D. E.; Phelps, M. E. C-11 labeled palmitic acid for the noninvasive evaluation of regional myocardial fatty acid metabolism with positron-computed tomography. Am. Heart J. 1982, 103, 532– 547, DOI: 10.1016/0002-8703(82)90341-6[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL387ls1yluw%253D%253D&md5=0726cccf15ea87ec87526641d9ca0090C- 11 labeled palmitic acid for the noninvasive evaluation of regional myocardial fatty acid metabolism with positron-computed tomography. I. Kinetics of C- 11 palmitic acid in normal myocardiumSchon H R; Schelbert H R; Robinson G; Najafi A; Huang S C; Hansen H; Barrio J; Kuhl D E; Phelps M EAmerican heart journal (1982), 103 (4 Pt 1), 532-47 ISSN:0002-8703.There is no expanded citation for this reference.
- 209Angsten, G.; Valind, S.; Takalo, R.; Neu, H.; Meurling, S.; Långström, B. Inhibition of carnitine-acyl transferase I by oxfenicine studied in vivo with [11C]-labeled fatty acids. Nucl. Med. Biol. 2005, 32, 495– 503, DOI: 10.1016/j.nucmedbio.2005.03.003[Crossref], [PubMed], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvVWmur8%253D&md5=568d6d4a9e3a076d2998a6ffa5067856Inhibition of carnitine-acyl transferase I by oxfenicine studied in vivo with [11C]-labeled fatty acidsAngsten, Gertrud; Valind, Sven; Takalo, Reijo; Neu, Henrik; Meurling, Staffan; Langstroem, BengtNuclear Medicine and Biology (2005), 32 (5), 495-503CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)Methods: Anesthetized pigs were studied with [11C]-labeled fatty acids (FAs) with carbon chain length ranging from 8 to 16 carbon atoms, during control conditions and during inhibition of carnitine-palmitoyl transferase I (CPT I) with oxfenicine. The myocardial uptake of [11C]-FAs from blood was measured together with the relative distribution of [11C]-acyl-CoA between rapid mitochondrial oxidn. and incorporation into slow turnover lipid pools in the heart. Results: During baseline conditions, the fractional oxidative utilization of palmitate was almost as high as that of carnitine-independent short-chain FAs, unless the carnitine shuttle was inhibited by high levels of lactate. Inhibition of CPT I almost completely blocked the oxidative pathway for palmitic acid and reduced the fractional oxidative utilization, while the rate of oxidative metab. of acyl-CoA was unaffected. Conclusions: [11C]-Labeled FAs allow rapid oxidn. to be well sepd. from esterification into slow turnover lipid pools in the heart of anesthetized pigs. The fractional oxidative utilization of [11C]-palmitate serves well to characterize, in vivo, the carnitine-dependent transfer of long-chain FAs.
- 210Ter-Pogossian, M. M.; Klein, M. S.; Markham, J.; Roberts, R.; Sobel, B. E. Regional assessment of myocardial metabolic integrity in vivo by positron-emission tomography with 11C-labeled palmitate. Circulation 1980, 61, 242– 255, DOI: 10.1161/01.CIR.61.2.242[Crossref], [PubMed], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3c%252FptVemtg%253D%253D&md5=1db69371daca17cc08c9aa7f9b49b294Regional assessment of myocardial metabolic integrity in vivo by positron-emission tomography with 11C-labeled palmitateTer-Pogossian M M; Klein M S; Markham J; Roberts R; Sobel B ECirculation (1980), 61 (2), 242-55 ISSN:0009-7322.There is no expanded citation for this reference.
- 211Geltman, E. M. Metabolic imaging of patients with cardiomyopathy. Circulation 1991, 84 (Suppl. 3), I265– 272
- 212Aikawa, T.; Naya, M.; Manabe, O.; Obara, M.; Matsushima, S.; Tamaki, N.; Tsutsui, H. Incidental focal myocardial (18)F-FDG uptake indicating asymptomatic coronary artery disease. J. Nucl. Cardiol. 2016, 23, 596– 598, DOI: 10.1007/s12350-015-0258-5[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC287itlymtg%253D%253D&md5=4f26d1393807e36d7fba6b00fe669ad4Incidental focal myocardial (18)F-FDG uptake indicating asymptomatic coronary artery diseaseAikawa Tadao; Naya Masanao; Obara Masahiko; Matsushima Shouji; Tsutsui Hiroyuki; Manabe Osamu; Tamaki NagaraJournal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology (2016), 23 (3), 596-8 ISSN:.There is no expanded citation for this reference.
- 213Ohira, H.; deKemp, R.; Pena, E.; Davies, R. A.; Stewart, D. J.; Chandy, G.; Contreras-Dominguez, V.; Dennie, C.; Mc Ardle, B.; Mc Klein, R.; Renaud, J. M.; DaSilva, J. N.; Pugliese, C.; Dunne, R.; Beanlands, R.; Mielniczuk, L. M. Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: A potential mechanism for a maladaptive right ventricular response. Eur. Heart J. Cardiovasc Imaging. 2016, 17, 1424– 1431, DOI: 10.1093/ehjci/jev136[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbitVCitg%253D%253D&md5=9d46972e97b143ab13890f6eee35b274Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: a potential mechanism for a maladaptive right ventricular responseOhira Hiroshi; deKemp Robert; Davies Ross A; Stewart Duncan J; Mc Ardle Brian; Mc Klein Ran; Renaud Jennifer M; DaSilva Jean N; Pugliese Carolyn; Dunne Rosemary; Beanlands Rob; Mielniczuk Lisa M; Pena Elena; Dennie Carole; Beanlands Rob; Pena Elena; Stewart Duncan J; Chandy George; Contreras-Dominguez Vladimir; Dennie Carole; Chandy George; Contreras-Dominguez VladimirEuropean heart journal cardiovascular Imaging (2016), 17 (12), 1424-1431 ISSN:.AIMS: We investigated the role of metabolic alterations in the development of a maladaptive right ventricular (RV) response in pulmonary arterial hypertension (PAH), which has not previously been undertaken. This study evaluated relationships between glucose and fatty acid metabolism obtained using PET with invasive pulmonary haemodynamics, RV measurements, and RV function to gain insight into the mechanism of RV maladaptation. METHODS AND RESULTS: Seventeen consecutive PAH patients (mean age 56 ± 15) who underwent right heart catheterization [mean pulmonary arterial pressure (mPAP) 43 ± 12 mmHg] had cardiac 18F-fluoro-2-deoxyglucose (FDG) and (18)F-fluoro-6-thioheptadecanoic acid (FTHA) PET imaging. RV and left ventricular (LV) FDG and FTHA uptake standard uptake values (SUVs) were measured. The SUV was corrected for the partial volume effect (SUVPVE) based on cardiac magnetic resonance imaging (CMR). Right ventricular ejection fraction (RVEF) was determined by CMR. There was a significant positive correlation between mPAP and RV/LV FDG SUVPVE (r = 0.68, P = 0.003), and the ratio of RV/LV FDG SUV : RV/LV FTHA SUV (r = 0.60, P = 0.02). RVEF was negatively correlated with RV/LV FDG SUVPVE uptake (r = -0.56, P = 0.02) and RV/LV FTHA SUVPVE (r = -0.62, P = 0.019). CONCLUSION: Increased pulmonary arterial pressures are associated with increases in the ratio of FDG/FTHA uptake in the RV. Inverse correlation between the uptake of the metabolic tracers and RV function may reflect a shift towards increased fatty acid oxidation and glycolysis associated with RV failure in maladaptive remodelling.
- 214SchÄfers, M.; Riemann, B.; Levkau, B.; Wichter, T.; SchÄfers, K.; Kopka, K.; Breithardt, G.; Schober, O. Current status and future applications of cardiac receptor imaging with positron emission tomography. Nucl. Med. Commun. 2002, 23, 113– 115, DOI: 10.1097/00006231-200202000-00001[Crossref], [PubMed], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD387lvVWksA%253D%253D&md5=5137405266aa61eb7aed3d02a50d5a26Current status and future applications of cardiac receptor imaging with positron emission tomographySchafers M; Riemann B; Levkau B; Wichter T; Schafers K; Kopka K; Breithardt G; Schober ONuclear medicine communications (2002), 23 (2), 113-5 ISSN:0143-3636.There is no expanded citation for this reference.
- 215Lautamäki, R.; Tipre, D.; Bengel, F. M. Cardiac sympathetic neuronal imaging using PET. Eur. J. Nucl. Med. Mol. Imaging 2007, 34 (S1), 74– 85, DOI: 10.1007/s00259-007-0442-1[Crossref], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVaqt7s%253D&md5=8560ffe14bd74bfcf8f03d00d66e1eeeCardiac sympathetic neuronal imaging using PETLautamaki, Riikka; Tipre, Dnyanesh; Bengel, Frank M.European Journal of Nuclear Medicine and Molecular Imaging (2007), 34 (Suppl. 1), S74-S85CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. Introduction Balance of the autonomic nervous system is essential for adequate cardiac performance, and alterations seem to play a key role in the development and progression of various cardiac diseases. PET as an imaging tool PET imaging of the cardiac autonomic nervous system has advanced extensively in recent years, and multiple pre- and postsynaptic tracers have been introduced. The high spatial and temporal resoln. of PET enables noninvasive quantification of neurophysiol. processes at the tissue level. Ligands for catecholamine receptors, along with radiolabeled catecholamines and catecholamine analogs, have been applied to det. involvement of sympathetic dysinnervation at different stages of heart diseases such as ischemia, heart failure, and arrhythmia. Review This review summarizes the recent findings in neurocardiol. PET imaging. Exptl. studies with several radioligands and clin. findings in cardiac dysautonomias are discussed.
- 216Delforge, J.; Syrota, A.; Lançon, J. P.; Nakajima, K.; Loc’h, C.; Janier, M.; Vallois, J. M.; Cayla, J.; Crouzel, C. Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical method. J. Nucl. Med. 1991, 32, 739– 748[PubMed], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlsFSlur8%253D&md5=fad620a42f6f71f921a9f68e0fe0ea03Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical methodDelforge, Jacques; Syrota, Andre; Lancon, Jean Pierre; Nakajima, Kenichi; Loc'h, Christian; Janier, Marc; Vallois, Jean Marie; Cayla, Jerome; Crouzel, ChristianJournal of Nuclear Medicine (1991), 32 (4), 739-48CODEN: JNMEAQ; ISSN:0161-5505.The in vivo quantification of myocardial β-adrenergic receptors was obtained in dogs using positron emission tomog. (PET). The ligand was racemic (±)[11C]CGP-12177, a very potent hydrophilic antagonist of the β-adrenergic receptor. A kinetic method was unsuitable because of the presence of metabolites which made the input function difficult to measure. A graphical method was proposed. The animals were injected with a trace amt. of (±)[11C]CGP-12177, followed 40 min later by a second injection of radioligand with a low-specific activity. An addnl. injection of an excess of unlabeled CGP-12177 was administered after 90 min and allowed for the estn. of the dissocn. rate const. The main advantage of this approach is that the results are obtained without measuring the input function and without estg. the metabolites. The av. value of B'max was 31 pmol/mL of tissue and the dissocn. const. was 0.014 min-1.
- 217Elsinga, P. H.; van Waarde, A.; Vaalburg, W. Receptor imaging in the thorax with PET. Eur. J. Pharmacol. 2004, 499, 1– 13, DOI: 10.1016/j.ejphar.2004.06.057[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnsFSqtbk%253D&md5=d756fb45cf02a246ae732728690ffa69Receptor imaging in the thorax with PETElsinga, Philip H.; van Waarde, Aren; Vaalburg, WillemEuropean Journal of Pharmacology (2004), 499 (1-2), 1-13CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)This review focuses on positron emission tomog. (PET) imaging of receptors in the sympathetic and the parasympathetic systems of heart and lung and highlights the human applications of PET. For the α-adrenoceptor, only [11C]GB67 (N2-{6-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(methyl)amino]hexyl}-N2-[11C]methyl-2-furamide hydrochloride) has been developed. Its potential for application in patients needs to be assessed. For both the β-adrenergic and the muscarinic systems, potent PET radioligands have been prepd. and evaluated in patients. It has been possible to measure receptor densities quant. in human heart {[11C]MQNB: [11C]methylquinuclidinyl benzilate, [11C]CGP12177: S-(3'-t-butylamino-2'-hydroxypropoxy)-benzimidazol-2-[11C]one and [11C]CGP12388: (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one} and qual. in lung {[11C]VC002: N-[11C]-methyl-piperidin-4-yl-2-cyclohexyl-2-hydroxy-2-phenylacetate and [11C]CGP12177}. Besides these subtype nonselective radioligands, the development of compds. that are selective for one subtype are ongoing and have not found successful application in humans yet.
- 218de Jong, R. M.; Willemsen, A. T. M.; Slart, R. H. J. A.; Blanksma, P. K.; van Waarde, A.; Cornel, J. H.; Vaalburg, W.; van Veldhuisen, D. J.; Elsinga, P. H. Myocardial β-adrenoceptor downregulation in idiopathic dilated cardiomyopathy measured in vivo with PET using the new radioligand (S)-[11C]CGP12388. Eur. J. Nucl. Med. Mol. Imaging 2005, 32, 443– 447, DOI: 10.1007/s00259-004-1701-z[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtV2hs78%253D&md5=b6342e37669e287fa77b91b5440c778cMyocardial β-adrenoceptor downregulation in idiopathic dilated cardiomyopathy measured in vivo with PET using the new radioligand (S)-[11C]CGP12388de Jong, Richard M.; Willemsen, Antoon T. M.; Slart, Riemer H. J. A.; Blanksma, Paul K.; van Waarde, Aren; Cornel, Jan Hein; Vaalburg, Willem; van Veldhuisen, Dirk J.; Elsinga, Philip H.European Journal of Nuclear Medicine and Molecular Imaging (2005), 32 (4), 443-447CODEN: EJNMA6; ISSN:1619-7070. (Springer GmbH)The β-adrenoceptor (β-AR) plays an important role in heart failure. Recently, the new tracer (S)-[11C]CGP12388 has been developed. It displays excellent properties for investigation of the cardiac β-ARs in vivo with positron emission tomog. (PET). Furthermore, the simple prodn. method allows its use in a routine clin. setting. The aim of this study was to investigate whether decreased myocardial β-AR d. in patients with idiopathic dilated cardiomyopathy (IDC) can be estd. using (S)-[11C]CGP12388 PET. Myocardial β-AR d. was investigated in six patients with IDC and six age-matched healthy controls, using (S)-[11C]CGP12388 PET. β-AR densities of 5.4±1.3 pmol/g (mean ± SD) were obsd. in patients; these values were significantly lower than those obsd. in healthy controls (8.4±1.5 pmol/g, p<0.005). This study indicates that PET with (S)-[11C]CGP12388 is applicable for the measurement of myocardial β-AR d. in patients. A highly significant redn. in β-AR d. was found in patients with IDC compared with healthy controls.
- 219Naya, M.; Tsukamoto, T.; Morita, K.; Katoh, C.; Nishijima, K.; Komatsu, H.; Yamada, S.; Kuge, Y.; Tamaki, N.; Tsutsui, H. Myocardial beta-adrenergic receptor density assessed by 11C-CGP12177 PET predicts improvement of cardiac function after carvedilol treatment in patients with idiopathic dilated cardiomyopathy. J. Nucl. Med. 2009, 50, 220– 225, DOI: 10.2967/jnumed.108.056341[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjt1Clsb4%253D&md5=5dc05098be2c8f9b4d18a5ba32c9c0a6Myocardial β-adrenergic receptor density assessed by 11C-CGP12177 PET predicts improvement of cardiac function after carvedilol treatment in patients with idiopathic dilated cardiomyopathyNaya, Masanao; Tsukamoto, Takahiro; Morita, Koichi; Katoh, Chietsugu; Nishijima, Kenichi; Komatsu, Hiroshi; Yamada, Satoshi; Kuge, Yuji; Tamaki, Nagara; Tsutsui, HiroyukiJournal of Nuclear Medicine (2009), 50 (2), 220-225CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)We evaluated whether myocardial β-adrenergic receptor (β-AR) d., as detd. by 11C-CGP12177 PET, could predict improvement of cardiac function by β-blocker carvedilol treatment in patients with idiopathic dilated cardiomyopathy (IDC). Methods: Ten patients with IDC (left ventricular ejection fraction [LVEF] < 45%) were studied. Myocardial β-AR d. was estd. using 11C-CGP12177 PET before treatment with carvedilol. Changes of LVEF in response to dobutamine infusion (ΔLVEF-dobutamine) were also measured by echocardiog. Changes of LVEF (ΔLVEF-carvedilol) were evaluated after 20 mo of carvedilol treatment. Results: Baseline myocardial β-AR d. significantly correlated with ΔLVEF-carvedilol (r = -0.88, P < 0.001). In contrast, ΔLVEF-dobutamine did not correlate with ΔLVEF-carvedilol (P = 0.65). Myocardial β-AR d. was the significant multivariate independent predictor of ΔLVEF-carvedilol (β = -0.88, P < 0.001) among univariate predictors, including functional class (r = 0.76, P < 0.05), plasma norepinephrine (r = 0.85, P < 0.01), LVEF (r = -0.64, P < 0.05), and age as confounding factors. Furthermore, myocardial β-AR d. was significantly correlated with plasma norepinephrine (r = -0.79, P < 0.01) and LVEF (r = 0.70, P < 0.05). Conclusion: Myocardial β-AR d. is more tightly related to improvement of LVEF-carvedilol than is cardiac contractile reserve in patients with IDC. Patients with decreased myocardial β-AR have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may receive greater benefit from being treated by antiadrenergic drugs.
- 220Vallabhajosula, S. Molecular Imaging; Springer: Berlin, Heidelberg, 2009.
- 221Gutterman, D. D.; Morgan, D. A.; Miller, F. J. Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction. Circ. Res. 1992, 71, 960– 969, DOI: 10.1161/01.RES.71.4.960[Crossref], [PubMed], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK38zos1Kmsw%253D%253D&md5=5b8158953c9aeb5f2228d64a04ef4ba0Effect of brief myocardial ischemia on sympathetic coronary vasoconstrictionGutterman D D; Morgan D A; Miller F JCirculation research (1992), 71 (4), 960-9 ISSN:0009-7330.The purpose of the present study was to determine whether sympathetic coronary vasoconstrictor responses are altered after brief ischemia and reperfusion. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, left ventricular pressure, left ventricular dP/dt, anterior myocardial wall thickening, and left circumflex coronary artery (LCX) and left anterior descending coronary artery (LAD) blood flow velocities. Changes in coronary vascular resistance were recorded during intravenous bolus doses of norepinephrine and bilateral electrical stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, electrical stimulation of the stellate ganglia increased coronary vascular resistance in the LAD and LCX beds by 38 +/- 5% and 39 +/- 5%, respectively. After a 15-minute LAD occlusion, repeat electrical stimulation produced increases in coronary resistance of 16 +/- 3% and 45 +/- 8%, respectively (p less than 0.05 for the LAD before versus after the occlusion). The peak increase in coronary vascular resistance to two doses of norepinephrine was unchanged. After a shorter period of myocardial ischemia (7 minutes), similar increase in coronary resistance to stellate stimulation were observed before (27 +/- 4%) and after (26 +/- 6%) myocardial ischemia. The mechanism of this impaired sympathetic coronary vasoconstriction was further tested by examining the responses to bretylium and tyramine. Brief ischemia did not alter the coronary constrictor responses to either bretylium or tyramine, suggesting that mechanisms governing prejunctional release of norepinephrine are intact in the postischemic coronary arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)
- 222Raffel, D. M.; Chen, W.; Sherman, P. S.; Gildersleeve, D. L.; Jung, Y.-W. Dependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter density. J. Nucl. Med. 2006, 47, 1490– 1496[PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVCmtLbF&md5=3f08f8090a5d9660d3ef8308ef3f357bDependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter densityRaffel, David M.; Chen, Wei; Sherman, Phillip S.; Gildersleeve, David L.; Jung, Young-WoonJournal of Nuclear Medicine (2006), 47 (9), 1490-1496CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)The norepinephrine analog 11C-meta-hydroxyephedrine (HED) is used with PET to map the regional distribution of cardiac sympathetic neurons. HED is rapidly transported into sympathetic neurons by the norepinephrine transporter (NET) and stored in vesicles. Although much is known about the neuronal mechanisms of HED uptake and retention, there is little information about the functional relationship between HED retention and cardiac sympathetic nerve d. The goal of this study was to characterize the dependence of HED retention on nerve d. in rats with graded levels of cardiac denervation induced chem. with the neurotoxin 6-hydroxydopamine (6-OHDA). Methods: Thirty male Sprague-Dawley rats were divided into 6 groups, and each group was administered a different dose of 6-OHDA: 0 (controls), 7, 11, 15, 22, and 100 mg/kg i.p. One day after 6-OHDA injection, HED (3.7-8.3 MBq) was injected i.v. into each animal and HED concns. in heart and blood at 30 min after injection were detd. Heart tissues were frozen and later processed by tissue homogenization and differential centrifugation into a membrane prepn. for in vitro measurement of cardiac NET d. A satn. binding assay using 3H-mazindol as the radioligand was used to measure NET d. (max. no. of binding sites [Bmax], fmol/mg protein) for each heart. Results: In control animals, NET Bmax was 388 ± 23 fmol/mg protein and HED heart uptake (HU) at 30 min was 2.89% ± 0.35 %ID/g (%ID/g is percentage injected dose per g tissue). The highest 6-OHDA dose of 100 mg/kg caused severe cardiac denervation, decreasing both NET Bmax and HED HU to 8% of their control values. Comparing values for all doses of 6-OHDA, HED retention had a strong linear correlation with NET d.: HU = 0.0077Bmax - 0.028, r2 = 0.95. Conclusion: HED retention is linearly dependent on NET d. in rat hearts that have been chem. denervated with 6-OHDA, suggesting that HED retention is a good surrogate measure of NET d. in the rat heart. This finding is discussed in relation to clin. observations of the dependence of HED retention on cardiac nerve d. in human subjects using PET.
- 223Fallavollita, J. A.; Luisi, A. J.; Michalek, S. M.; Valverde, A. M.; deKemp, R. A.; Haka, M. S.; Hutson, A. D.; Canty, J. M. Prediction of arrhythmic events with positron emission tomography: PAREPET study design and methods. Contemp. Clin. Trials 2006, 27, 374– 388, DOI: 10.1016/j.cct.2006.03.005[Crossref], [PubMed], [CAS], Google Scholar223Prediction of arrhythmic events with positron emission tomography: PAREPET study design and methodsFallavollita James A; Luisi Andrew J Jr; Michalek Suzanne M; Valverde Arturo M; deKemp Robert A; Haka Michael S; Hutson Alan D; Canty John M JrContemporary clinical trials (2006), 27 (4), 374-88 ISSN:1551-7144.BACKGROUND: In medically-treated patients with ischemic cardiomyopathy, myocardial viability is associated with a worse prognosis than scar. The risk is especially great with hibernating myocardium (chronic regional dysfunction with reduced resting flow), and the excess mortality appears to be due to sudden cardiac death (SCD). Hibernating myocardium also results in sympathetic nerve dysfunction, which has been independently associated with risk of SCD. OBJECTIVES: PAREPET is a prospective, observational cohort study funded by NHLBI. It is designed to determine whether hibernating myocardium and/or inhomogeneity of sympathetic innervation by positron emission tomography imaging identifies patients with ischemic cardiomyopathy who are at high risk for SCD and cardiovascular mortality. METHODS: Patients with documented ischemic cardiomyopathy, an ejection fraction ofhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28zpsVGltA%253D%253D&md5=de20a9f86547e5ac466b7c200023c0ec224Carrió, I. Cardiac neurotransmission imaging. J. Nucl. Med. 2001, 42, 1062– 1076[PubMed], [CAS], Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntVSmsL4%253D&md5=ec884220d7a94bb0154b9745e26d4cb0Cardiac neurotransmission imagingCarrio, IgnasiJournal of Nuclear Medicine (2001), 42 (7), 1062-1076CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review. Cardiac neurotransmission imaging with SPECT and PET allows in vivo assessment of presynaptic reuptake and neurotransmitter storage as well as of regional distribution and activity of postsynaptic receptors. In this way, the biochem. processes that occur during neurotransmission can be investigated in vivo at a micromolar level using radiolabeled neurotransmitters and receptor ligands. SPECT and PET of cardiac neurotransmission characterize myocardial neuronal function in primary cardioneuropathies, in which the heart has no significant structural abnormality, and in secondary cardioneuropathies caused by the metabolic and functional changes that take place in different diseases of the heart. In patients with heart failure, the assessment of sympathetic activity has important prognostic implications and will result in better therapy and outcome. In diabetic patients, scintigraphic techniques allow the detection of autonomic neuropathy in early stages of the disease. In conditions with a risk of sudden death, such as idiopathic ventricular tachycardia and arrhythmogenic right ventricular cardiomyopathy, PET and SPECT reveal altered neuronal function when no other structural abnormality is seen. In patients with ischemic heart disease, heart transplantation, drug-induced cardiotoxicity, and dysautonomias, assessment of neuronal function can help characterize the disease and improve prognostic stratification. Future directions include the development of tracers for new types of receptors, the targeting of second messenger mols., and the early assessment of cardiac neurotransmission in genetically predisposed subjects for prevention and early treatment of heart failure.225Luisi, A. J.; Suzuki, G.; Dekemp, R.; Haka, M. S.; Toorongian, S. A.; Canty, J. M.; Fallavollita, J. A. Regional 11C-hydroxyephedrine retention in hibernating myocardium: Chronic inhomogeneity of sympathetic innervation in the absence of infarction. J. Nucl. Med. 2005, 46, 1368– 1374[PubMed], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVGlsb0%253D&md5=140c0304caad159723b54473a8926f96Regional 11C-hydroxyephedrine retention in hibernating myocardium: chronic inhomogeneity of sympathetic innervation in the absence of infarctionLuisi, Andrew J., Jr.; Suzuki, Gen; de Kemp, Robert; Haka, Michael S.; Toorongian, Steven A.; Canty, John M., Jr.; Fallavollita, James A.Journal of Nuclear Medicine (2005), 46 (8), 1368-1374CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)The authors have previously shown that ex vivo counting of 131I-meta-iodobenzylguanidine can identify regional redns. in sympathetic norepinephrine uptake in pigs with hibernating myocardium. However, nonneuronal uptake limited relative differences between regions and would preclude accurate assessment with conventional imaging. The authors therefore hypothesized that the superior specificity of the positron-emitting isotope 11C-hydroxyephedrine (HED) would facilitate the imaging of regional differences, and they designed this study to det. whether altered uptake of norepinephrine by sympathetic nerves in viable, dysfunctional myocardium can be imaged in vivo and to det. the temporal progression and stability of sympathetic dysinnervation in hibernating myocardium. Pigs (n = 15) were chronically instrumented with a 1.5-mm stenosis of the left anterior descending coronary artery, a procedure that was previously shown to produce viable chronically dysfunctional myocardium with reduced resting flow, or hibernating myocardium, after 3 mo. Physiol. studies and HED PET were performed 1-5 mo later with the animals in the closed-chest sedated state. One animal with a myocardial infarct was analyzed sep. After 3 mo, anterior hypokinesis developed (wall thickening, 32% ± 4% vs. 60% ± 4%, P < 0.001), with redns. in resting flow (subendocardial flow, 0.81 ± 0.11 vs. 1.20 ± 0.18 mL/min/g, P < 0.05) and a crit. redn. in subendocardial flow reserve (subendocardial adenosine flow, 0.53 ± 0.20 vs. 3.96 ± 0.43 mL/min/g, P < 0.001). Extensive defects in HED uptake were found for hibernating myocardium, with regional retention ∼50% lower than that in normally perfused remote myocardium (0.035 ± 0.002 vs. 0.066 ± 0.002 min-1, P < 0.001). Relative HED uptake (left anterior descending coronary artery/remote) was lower in chronically instrumented animals than in control animals (n = 4, P < 0.001) and animals studied 1 mo after instrumentation (n = 2, P < 0.05). The regional redn. in sympathetic nerve function was persistent and unaltered for at least 2 mo after the development of hibernating myocardium. Hibernating myocardium is assocd. with persistent redns. in regional uptake of norepinephrine by sympathetic nerves. The inhomogeneity in sympathetic innervation in viable dysfunctional myocardium is similar to that occurring after myocardial infarction and may contribute to arrhythmic death in patients with ischemic cardiomyopathy.226Raffel, D. M.; Koeppe, R. A.; Jung, Y.-W.; Gu, G.; Jang, K. S.; Sherman, P. S.; Quesada, C. A. Quantification of cardiac sympathetic nerve density with N-11C-guanyl-meta-octopamine and tracer kinetic analysis. J. Nucl. Med. 2013, 54, 1645– 1652, DOI: 10.2967/jnumed.113.120659[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFyntr7I&md5=c68fc3c0b6b45fa45914e4e61bb6c4d0Quantification of cardiac sympathetic nerve density with N-11C-guanyl-meta-octopamine and tracer kinetic analysisRaffel, David M.; Koeppe, Robert A.; Jung, Yong-Woon; Gu, Guie; Jang, Keun Sam; Sherman, Phillip S.; Quesada, Carole A.Journal of Nuclear Medicine (2013), 54 (9), 1645-1652CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)Most cardiac sympathetic nerve radiotracers are substrates of the norepinephrine transporter (NET). Existing tracers such as 123I-metaiodobenzylguanidine (123I-MIBG) and 11C-(-)-meta-hydroxy-ephedrine (11C-HED) are flow-limited tracers because of their rapid NET transport rates. This prevents successful application of kinetic anal. techniques and causes semiquant. measures of tracer retention to be insensitive to mild-to-moderate nerve losses. N-11C-guanyl-(-)-meta-octopamine (11C-GMO) has a much slower NET transport rate and is trapped in storage vesicles. The goal of this study was to det. whether analyses of 11C-GMO kinetics could provide robust and sensitive measures of regional cardiac sympathetic nerve densities. Methods: PET studies were performed in a rhesus macaque monkey under control conditions or after i.v. infusion of the NET inhibitor desipramine (DMI). Five desipramine dose levels were used to establish a range of available cardiac NET levels. Compartmental modeling of 11C-GMO kinetics yielded ests. of the rate consts. K1 (mL/min/g), k2 (min-1), and k3 (min-1). These values were used to calc. a net uptake rate const. Ki (mL/min/g) = (K1k3)/(k2 + k3). In addn., Patlak graphical analyses of 11C-GMO kinetics yielded Patlak slopes Kp (mL/min/g), which represent alternative measurements of the net uptake rate const. Ki. 11C-GMO kinetics in isolated rat hearts were also measured for comparison with other tracers. Results: In isolated rat hearts, the neuronal uptake rate of 11C-GMO was 8 times slower than 11C-HED and 12 times slower than 11C-MIBG. 11C-GMO also had a long neuronal retention time (>200 h). Compartmental modeling of 11C-GMO kinetics in the monkey heart proved stable under all conditions. Calcd. net uptake rate consts. Ki tracked desipramine-induced redns. of available NET in a dose-dependent manner, with a half maximal inhibitory concn. (IC50) of 0.087 ± 0.012 mg of desipramine per kg. Patlak anal. provided highly linear Patlak plots, and the Patlak slopes Kp also declined in a dose-dependent manner (IC50 = 0.068 ± 0.010 mg of desipramine per kg). Conclusion: Compartmental modeling and Patlak anal. of 11C-GMO kinetics each provided quant. parameters that accurately tracked changes in cardiac NET levels. These results strongly suggest that PET studies with 11C-GMO can provide robust and sensitive quant. measures of regional cardiac sympathetic nerve densities in human hearts.227Thackeray, J. T.; Bengel, F. M. PET imaging of the autonomic nervous system. Q. J. Nucl. Med. Mol. Imaging 2016, 60, 362– 382[PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szovVOgtg%253D%253D&md5=d007fcdc6206ae3f8400b8bf1369f786PET imaging of the autonomic nervous systemThackeray James T; Bengel Frank MThe quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.. (2016), 60 (4), 362-82 ISSN:.The autonomic nervous system is the primary extrinsic control of heart rate and contractility, and is subject to adaptive and maladaptive changes in cardiovascular disease. Consequently, noninvasive assessment of neuronal activity and function is an attractive target for molecular imaging. A myriad of targeted radiotracers have been developed over the last 25 years for imaging various components of the sympathetic and parasympathetic signal cascades. While routine clinical use remains somewhat limited, a number of larger scale studies in recent years have supplied momentum to molecular imaging of autonomic signaling. Specifically, the findings of the ADMIRE HF trial directly led to United States Food and Drug Administration approval of 123I-metaiodobenzylguanidine (MIBG) for Single Photon Emission Computed Tomography (SPECT) assessment of sympathetic neuronal innervation, and comparable results have been reported using the analogous PET agent 11C-meta-hydroxyephedrine (HED). Due to the inherent capacity for dynamic quantification and higher spatial resolution, regional analysis may be better served by PET. In addition, preliminary clinical and extensive preclinical experience has provided a broad foundation of cardiovascular applications for PET imaging of the autonomic nervous system. Recent years have witnessed the growth of novel quantification techniques, expansion of multiple tracer studies, and improved understanding of the uptake of different radiotracers, such that the transitional biology of dysfunctional subcellular catecholamine handling can be distinguished from complete denervation. As a result, sympathetic neuronal molecular imaging is poised to play a role in individualized patient care, by stratifying cardiovascular risk, visualizing underlying biology, and guiding and monitoring therapy.228Sinusas, A. J.; Lazewatsky, J.; Brunetti, J.; Heller, G.; Srivastava, A.; Liu, Y.-H.; Sparks, R.; Puretskiy, A.; Lin, S.; Crane, P.; Carson, R. E.; Lee, L. V. Biodistribution and radiation dosimetry of LMI1195: First-in-human study of a novel 18F-labeled tracer for imaging myocardial innervation. J. Nucl. Med. 2014, 55, 1445– 1451, DOI: 10.2967/jnumed.114.140137[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVSrur3M&md5=ba681968cd70fbf95871a76c759dd644Biodistribution and radiation dosimetry of LMI1195: first-in-human study of a Novel 18F-labeled tracer for imaging myocardial innervationSinusas, Albert J.; Lazewatsky, Joel; Brunetti, Jacqueline; Heller, Gary; Srivastava, Ajay; Liu, Yi-Hwa; Sparks, Richard; Puretskiy, Andrey; Lin, Shu-fei; Crane, Paul; Carson, Richard E.; Lee, L. VeronicaJournal of Nuclear Medicine (2014), 55 (9), 1445-1451CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)A novel 18F-labeled ligand for the norepinephrine transporter (N-[3-bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine [LMI1195]) is in clin. development for mapping cardiac nerve terminals in vivo using PET. Human safety, whole-organ biodistribution, and radiation dosimetry of LMI1195 were evaluated in a phase 1 clin. trial. Methods: Twelve healthy subjects at 3 clin. sites were injected i.v. with 150-250 MBq of LMI1195. Dynamic PET images were obtained over the heart for 10 min, followed by sequential whole-body images for approx. 5 h. Blood samples were obtained, and heart rate, ECG, and blood pressure were monitored before and during imaging. Residence times were detd. from multiexponential regression of organ region-of-interest data normalized by administered activity (AA). Radiation dose ests. were calcd. using OLINDA/EXM. Myocardial, lung, liver, and blood-pool standardized uptake values were detd. at different time intervals. Results: No adverse events due to LMI1195 were seen. Blood radioactivity cleared quickly, whereas myocardial uptake remained stable and uniform throughout the heart over 4 h. Liver and lung activity cleared relatively rapidly, providing favorable target-to-background ratios for cardiac imaging. The urinary bladder demonstrated the largest peak uptake (18.3% AA), followed by the liver (15.5% AA). The mean ED was 0.026 ± 0.0012 mSv/MBq. Approx. 1.6% AA was seen in the myocardium initially, remaining above 1.5% AA (decay-cor.) through 4 h after injection. The myocardium-to-liver ratio was approx. unity initially, increasing to more than 2 at 4 h. Conclusion: These preliminary data suggest that LMI1195 is well tolerated and yields a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. The kinetics of myocardial and adjacent organ activity suggest that cardiac imaging should be possible with acceptable patient radiation dose.229Pacher, P.; Steffens, S.; Haskó, G.; Schindler, T. H.; Kunos, G. Cardiovascular effects of marijuana and synthetic cannabinoids: The good, the bad, and the ugly. Nat. Rev. Cardiol. 2018, 15, 151– 166, DOI: 10.1038/nrcardio.2017.130[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2isLnN&md5=9f1ce4c6c3173e5c9c4dc19a307c99d0Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the uglyPacher, Pal; Steffens, Sabine; Hasko, Gyorgy; Schindler, Thomas H.; Kunos, GeorgeNature Reviews Cardiology (2018), 15 (3), 151-166CODEN: NRCAE6; ISSN:1759-5002. (Nature Research)Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ9-tetrahydrocannabinol (THC), is an agonist of both CB1R and CB2R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogs might be the underlying cause of severe cardiovascular events and pathologies.230Valenta, I.; Varga, Z. V.; Valentine, H.; Cinar, R.; Horti, A.; Mathews, W. B.; Dannals, R. F.; Steele, K.; Kunos, G.; Wahl, R. L.; Pomper, M. G.; Wong, D. F.; Pacher, P.; Schindler, T. H. Feasibility evaluation of myocardial cannabinoid type 1 receptor imaging in obesity. JACC: Cardiovascular Imaging. 2018, 11, 320– 332, DOI: 10.1016/j.jcmg.2017.11.019[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mvos1aqtw%253D%253D&md5=0613321cb418452cbb16c8bb38e15207Feasibility Evaluation of Myocardial Cannabinoid Type 1 Receptor Imaging in Obesity: A Translational ApproachValenta Ines; Valentine Heather; Horti Andrew; Mathews William B; Dannals Robert F; Pomper Martin G; Wong Dean F; Varga Zoltan V; Cinar Resat; Kunos George; Steele Kimberley; Wahl Richard L; Pacher Pal; Schindler Thomas HJACC. Cardiovascular imaging (2018), 11 (2 Pt 2), 320-332 ISSN:.OBJECTIVES: The aim of this study was to evaluate the feasibility of targeted imaging of myocardial cannabinoid type 1 receptor (CB1-R) and its potential up-regulation in obese mice with translation to humans using [(11)C]-OMAR and positron emission tomography (PET)/computed tomography (CT). BACKGROUND: Activation of myocardial CB1-R by endocannabinoids has been implicated in cardiac dysfunction in diabetic mice. Obesity may lead to an up-regulation of myocardial CB1-R, potentially providing a mechanistic link between obesity and the initiation and/or progression of cardiomyopathy. METHODS: Binding specificity of [(11)C]-OMAR to CB1-R was investigated by blocking studies with rimonabant in mice. The heart was harvested from each mouse, and its radioactivity was determined by γ-counter. Furthermore, [(11)C]-OMAR dynamic micro-PET/CT was carried out in obese and normal-weight mice. Ex vivo validation was performed by droplet digital polymerase chain reaction (absolute quantification) and RNAscope Technology (an in situ ribonucleic acid analysis platform). Subsequently, myocardial CB1-R expression was probed noninvasively with intravenous injection of CB1-R ligand [(11)C]-OMAR and PET/CT in humans with advanced obesity and normal-weight human control subjects, respectively. RESULTS: Rimonabant significantly blocked OMAR uptake in the heart muscle compared with vehicle, signifying specific binding of OMAR to the CB1-R in the myocardium. The myocardial OMAR retention quantified by micro-PET/CT in mice was significantly higher in obese compared with normal-weight mice. Absolute quantification of CB1-R gene expression with droplet digital polymerase chain reaction and in situ hybridization confirmed CB1-R up-regulation in all major myocardial cell types (e.g., cardiomyocytes, endothelium, vascular smooth muscle cells, and fibroblasts) of obese mice. Obese mice also had elevated myocardial levels of endocannabinoids anandamide and 2-arachidonoylglycerol compared with lean mice. Translation to humans revealed higher myocardial OMAR retention in advanced obesity compared with normal-weight subjects. CONCLUSIONS: Noninvasive imaging of cardiac CB1-R expression in obesity is feasible applying [(11)C]-OMAR and PET/CT. These results may provide a rationale for further clinical testing of CB1-R-targeted molecular imaging in cardiometabolic diseases.231Fukushima, K.; Bravo, P. E.; Higuchi, T.; Schuleri, K. H.; Lin, X.; Abraham, M. R.; Xia, J.; Mathews, W. B.; Dannals, R. F.; Lardo, A. C.; Szabo, Z.; Bengel, F. M. Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin II type 1 receptors. J. Am. Coll. Cardiol. 2012, 60, 2527– 2534, DOI: 10.1016/j.jacc.2012.09.023[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCrs7fL&md5=3f7730bcb9d5ba6e92d2a90c7c392f3aMolecular Hybrid Positron Emission Tomography/Computed Tomography Imaging of Cardiac Angiotensin II Type 1 ReceptorsFukushima, Kenji; Bravo, Paco E.; Higuchi, Takahiro; Schuleri, Karl H.; Lin, Xiaoping; Abraham, M. Roselle; Xia, Jinsong; Mathews, William B.; Dannals, Robert F.; Lardo, Albert C.; Szabo, Zsolt; Bengel, Frank M.Journal of the American College of Cardiology (2012), 60 (24), 2527-2534CODEN: JACCDI; ISSN:0735-1097. (Elsevier Inc.)The goal of this study was to explore the feasibility of targeted imaging of the angiotensin II type 1 receptor (AT1R) in cardiac tissue, using clin. hybrid positron emission tomog./computed tomog. (PET/CT). AT1R is an attractive imaging target due to its key role in various cardiac pathologies, including post-infarct left ventricular remodeling. Using the novel AT1R ligand [11C]-KR31173, dynamic PET/CT was performed in young farm pigs under healthy conditions (n = 4) and 3 to 4 wk after exptl. myocardial infarction (n = 5). Ex vivo validation was carried out by immunohistochem. and polymerase chain reaction. First-in-man application was performed in 4 healthy volunteers at baseline and under AT1R blocking. In healthy pigs, myocardial KR31173 retention was detectable, regionally homogeneous, and specific for AT1R, as confirmed by blocking expts. Metab. in plasma was low (85 ± 2% of intact tracer after 60 min). After myocardial infarction, KR31173 retention, cor. for regional perfusion, revealed AT1R up-regulation in the infarct area relative to remote myocardium, whereas retention was elevated in both regions when compared with myocardium of healthy controls (8.7 ± 0.8% and 7.1 ± 0.3%/min vs. 5.8 ± 0.4%/min for infarct and remote, resp., vs. healthy controls; p < 0.01 each). Postmortem anal. confirmed AT1R up-regulation in remote and infarct tissue. First-in-man application was safe, and showed detectable and specific myocardial KR31173 retention, albeit at a lower level than pigs (left ventricular av. retention: 1.2 ± 0.1%/min vs. 4.4 ± 1.2%/min for humans vs. pigs; p = 0.04). Noninvasive imaging of cardiac AT1R expression is feasible using clin. PET/CT technol. Results provide a rationale for broader clin. testing of AT1R-targeted mol. imaging.232Schindler, T. H.; Dilsizian, V. Cardiac positron emission tomography/computed tomography imaging of the renin-angiotensin system in humans holds promise for image-guided approach to heart failure therapy. J. Am. Coll. Cardiol. 2012, 60, 2535– 2538, DOI: 10.1016/j.jacc.2012.09.022[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s7ktVegtA%253D%253D&md5=2f2c4f977b2acf5c1672ebfa90210e30Cardiac positron emission tomography/computed tomography imaging of the Renin-Angiotensin system in humans holds promise for image-guided approach to heart failure therapySchindler Thomas H; Dilsizian VaskenJournal of the American College of Cardiology (2012), 60 (24), 2535-8 ISSN:.There is no expanded citation for this reference.233Higuchi, T.; Fukushima, K.; Xia, J.; Mathews, W. B.; Lautamaki, R.; Bravo, P. E.; Javadi, M. S.; Dannals, R. F.; Szabo, Z.; Bengel, F. M. Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury. J. Nucl. Med. 2010, 51, 1956– 1961, DOI: 10.2967/jnumed.110.079855[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbos1ynsg%253D%253D&md5=a8b65e27ea573fc2012f44310372b52fRadionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injuryHiguchi Takahiro; Fukushima Kenji; Xia Jinsong; Mathews William B; Lautamaki Riikka; Bravo Paco E; Javadi Mehrbod S; Dannals Robert F; Szabo Zsolt; Bengel Frank MJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2010), 51 (12), 1956-61 ISSN:.UNLABELLED: The renin-angiotensin system (RAS) mediates proapoptotic, profibrotic, and proinflammatory processes in maladaptive conditions. Activation after myocardial infarction may initialize and promote cardiac remodeling. Using a novel positron-emitting ligand, we sought to determine the presence and time course of regional myocardial upregulation of the angiotensin II type 1 receptor (AT1R) and the blocking efficacy of various anti-RAS agents. METHODS: In male Wistar rats (n = 31), ischemia-reperfusion damage was induced by 20- to 25-min ligation of the left coronary artery. The AT1R blocker (11)C-2-butyl-5-methoxymethyl-6-(1-oxopyridin-2-yl)-3-[[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine ((11)C-KR31173) was injected intravenously at different times until 6 mo after surgery and sacrifice. Autoradiography, histology, and immunohistochemistry were performed for ex vivo validation. Additional in vivo PET was conducted in 3 animals. A second series of experiments (n = 16) compared untreated animals with animals treated with oral valsartan (50 mg/kg/d), oral enalapril (10 mg/kg/d), and complete intravenous blockage (SK-1080, 2 mg/kg, 10 min before imaging). RESULTS: Transient regional AT1R upregulation was detected in the infarct area, with a peak at 1-3 wk after surgery (autoradiographic infarct-to-remote ratio, 1.07 ± 0.09, 1.68 ± 0.34, 2.54 ± 0.40, 2.98 ± 0.70, 3.16 ± 0.57, 1.86 ± 0.65, and 1.28 ± 0.27 at control, day 1, day 3, week 1, week 3, month 3, and month 6, respectively). The elevated uptake of (11)C-KR31173 in the infarct area was detectable by small-animal PET in vivo, and it was blocked completely by intravenous SK-1080. Although oral treatment with enalapril did not reduce focal tracer uptake, oral valsartan resulted in partial blockade (infarct-to-remote ratio, 2.94 ± 0.52, 2.88 ± 0.60, 2.07 ± 0.25, and 1.26 ± 0.10 for no treatment, enalapril, valsartan, and SK-1080, respectively). CONCLUSION: After ischemic myocardial damage in a rat model, transient regional AT1R upregulation is detectable in the infarct area using (11)C-KR31173. Inhibitory effects of the clinical AT1R blocker valsartan can be identified, whereas blockage of upstream angiotensin-converting enzyme with enalapril does not affect AT1R density. These results provide a rationale for subsequent testing of AT1R-targeted imaging to predict the risk for ventricular remodeling and to monitor the efficacy of anti-RAS drug therapy.234Quercioli, A.; Montecucco, F.; Pataky, Z.; Thomas, A.; Ambrosio, G.; Staub, C.; Di Marzo, V.; Ratib, O.; Mach, F.; Golay, A.; Schindler, T. H. Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokines. Eur. Heart J. 2013, 34, 2063– 2073, DOI: 10.1093/eurheartj/eht085[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svlsFaqsg%253D%253D&md5=8e9a6284cbf573f2e1b086e0129d0ed6Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokinesQuercioli Alessandra; Montecucco Fabrizio; Pataky Zoltan; Thomas Aurelien; Ambrosio Giuseppe; Staub Christian; Di Marzo Vincenzo; Ratib Osman; Mach Francois; Golay Alain; Schindler Thomas HEuropean heart journal (2013), 34 (27), 2063-73 ISSN:.AIMS: To investigate the effect of surgical gastric bypass-induced weight loss and related alterations in endocannabinoids (ECs) and adipocytokine plasma levels on coronary circulatory dysfunction in morbidly obese (MOB) individuals. METHODS AND RESULTS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) from rest (ΔMBF) and during pharmacologically induced hyperaemia were measured with 13N-ammonia PET/CT in 18 MOB individuals with a body mass index (BMI) > 40 kg/m2 at baseline and after a median follow-up period of 22 months. Gastric bypass intervention decreased BMI from a median of 44.8 (inter-quartile range: 43.3, 48.2) to 30.8 (27.3, 34.7) kg/m2 (P < 0.0001). This decrease in BMI was accompanied by a marked improvement in endothelium-related ΔMBF to CPT and hyperaemic MBFs, respectively [0.34 (0.18, 0.41) from 0.03 (-0.08, 0.15) mL/g/min, P = 0.002; and 2.51 (2.17, 2.64) from 1.53 (1.39, 2.18) mL/g/min, P < 0.001]. There was an inverse correlation between decreases in plasma concentrations of the EC anandamide and improvement in ΔMBF to CPT (r = -0.59, P = 0.009), while increases in adiponectin plasma levels correlated positively with hyperaemic MBFs (r = 0.60, P = 0.050). Conversely, decreases in leptin plasma concentrations were not observed to correlate with the improvement in coronary circulatory function (r = 0.22, P = 0.400, and r = -0.31, P = 0.250). CONCLUSIONS: Gastric bypass-related reduction of BMI in MOB individuals beneficially affects coronary circulatory dysfunction. The dysbalance between ECs and adipocytokines appears to be an important determinant of coronary circulatory function in obesity.235Quercioli, A.; Pataky, Z.; Vincenti, G.; Makoundou, V.; Di Marzo, V.; Montecucco, F.; Carballo, S.; Thomas, A.; Staub, C.; Steffens, S.; Seimbille, Y.; Golay, A.; Ratib, O.; Harsch, E.; Mach, F.; Schindler, T. H. Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur. Heart J. 2011, 32, 1369– 1378, DOI: 10.1093/eurheartj/ehr029[Crossref], [PubMed], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntF2ht7Y%253D&md5=b3fa1b171901fb082f23aff18ffbeed5Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesityQuercioli, Alessandra; Pataky, Zoltan; Vincenti, Gabriella; Makoundou, Vincent; Di Marzo, Vincenzo; Montecucco, Fabrizio; Carballo, Sebastian; Thomas, Aurelien; Staub, Christian; Steffens, Sabine; Seimbille, Yann; Golay, Alain; Ratib, Osman; Harsch, Elisabetta; Mach, Francois; Schindler, Thomas H.European Heart Journal (2011), 32 (11), 1369-1378CODEN: EHJODF; ISSN:0195-668X. (Oxford University Press)Aims: Aim of this study was to evaluate a possible assocn. between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. Methods and results: Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacol. vasodilation with dipyridamole were measured with 13N-ammonia PET/CT. Study participants (n = 77) were divided into three groups based on their body mass index (BMI, kg/m2): control group 20≤ BMI <25 (n = 21); overweight group, 25≤ BMI <30 (n = 26); and obese group, BMI ≥30 (n = 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, resp. 0.68 (0.53, 0.78) vs. 0.56 0.47, 0.66 ng/mL, P = 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P = 0.806. The endothelium-related change in MBF during CPT from rest (ΔMBF) progressively declined in overweight and obese when compared with control group 0.21 (0.10, 0.27) and 0.09 (-0.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P = 0.010 and P = 0.0001, resp. Compared with controls, hyperemic MBFs were significantly lower in overweight and obese individuals 2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P = 0.007 and P = 0.042, resp. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with ΔMBF to CPT (r = -0.37, P = 0.046 and r = -0.48, P = 0.008) and hyperemic MBFs (r = -0.38, P = 0.052 and r = -0.45, P = 0.017), resp. Conclusions: Increased EC plasma levels of AEA and 2-AG are assocd. with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.236Pacher, P.; Kunos, G. Modulating the endocannabinoid system in human health and disease - successes and failures. FEBS J. 2013, 280, 1918– 1943, DOI: 10.1111/febs.12260[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmsFWgu7w%253D&md5=831af5bc7f9fc21acab7c517e58c7e74Modulating the endocannabinoid system in human health and disease - successes and failuresPacher, Pal; Kunos, GeorgeFEBS Journal (2013), 280 (9), 1918-1943CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)A review. The discovery of the endocannabinoid system, comprising the G-protein coupled cannabinoid 1 and 2 receptors (CB1/2), their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, has triggered an avalanche of exptl. studies implicating the endocannabinoid system in a growing no. of physiol./pathol. functions. These studies have also suggested that modulating the activity of the endocannabinoid system holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders; obesity/metabolic syndrome; cachexia; chemotherapy-induced nausea and vomiting; and tissue injury and pain, amongst others. However, clin. trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally-restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain, have introduced unexpected complexities, suggesting that a better understanding of the pathophysiol. role of the endocannabinoid system is required to devise clin. successful treatment strategies.237Rajesh, M.; Batkai, S.; Kechrid, M.; Mukhopadhyay, P.; Lee, W.-S.; Horvath, B.; Holovac, E.; Cinar, R.; Liaudet, L.; Mackie, K.; Hasko, G.; Pacher, P. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes 2012, 61, 716– 727, DOI: 10.2337/db11-0477[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XovFegurk%253D&md5=3eb168ce66bcbc292cf8e267497ff87fCannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathyRajesh, Mohanraj; Batkai, Sandor; Kechrid, Malek; Mukhopadhyay, Partha; Lee, Wen-Shin; Horvath, Bela; Holovac, Eileen; Cinar, Resat; Liaudet, Lucas; Mackie, Ken; Hasko, Gyorgy; Pacher, PalDiabetes (2012), 61 (3), 716-727CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)Endocannabinoids and cannabinoid 1 (CB1) receptors have been implicated in cardiac dysfunction, inflammation, and cell death assocd. with various forms of shock, heart failure, and atherosclerosis, in addn. to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB1 receptors in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH2-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion mol. 1, and vascular cell adhesion mol. 1), increased expression of CB1, advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT1R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isoenzyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). Pharmacol. inhibition or genetic deletion of CB1 receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathol. alterations. Activation of CB1 receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT1R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB1 receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.238Lim, S. L.; Lam, C. S. P.; Segers, V. F. M.; Brutsaert, D. L.; De Keulenaer, G. W. Cardiac endothelium–myocyte interaction: Clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur. Heart J. 2015, 36, 2050– 2060, DOI: 10.1093/eurheartj/ehv132[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFertrnF&md5=ae37c68fe6133b7f8c91527e8427ba64Cardiac endothelium-myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fractionLim, Shir Lynn; Lam, Carolyn S. P.; Segers, Vincent F. M.; Brutsaert, Dirk L.; De Keulenaer, Gilles W.European Heart Journal (2015), 36 (31), 2050-2060,2060b,2060c,2060dCODEN: EHJODF; ISSN:0195-668X. (Oxford University Press)Heart failure (HF) is an important global health problem with great socioeconomic burden. Outcomes remain sub-optimal. Endothelium-cardiomyocyte interactions play essential roles in cardiovascular homeostasis, and deranged endothelium-related signalling pathways have been implicated in the pathophysiol. of HF. In particular, disturbances in nitric oxide (NO)-mediated pathway and neuregulin-mediated pathway have been shown to contribute to the development of HF. These signalling pathways hold the potential as pathophysiol. targets for new HF therapies, and may aid in patient selection for future HF trials.239Paulus, W. J.; Tschöpe, C. A novel paradigm for heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 2013, 62, 263– 271, DOI: 10.1016/j.jacc.2013.02.092[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3snkslehtQ%253D%253D&md5=487286e6a7480237a3f14a783efb3476A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammationPaulus Walter J; Tschope CarstenJournal of the American College of Cardiology (2013), 62 (4), 263-71 ISSN:.Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.240Fish, K. M.; Hajjar, R. J. Myocardial cannabinoid receptor imaging in obesity. JACC: Cardiovascular Imaging. 2018, 11, 333– 335, DOI: 10.1016/j.jcmg.2017.12.001[Crossref], [PubMed], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mvos1aqtA%253D%253D&md5=9db693742957a67c8ed8099e3370938eMyocardial Cannabinoid Receptor Imaging in ObesityFish Kenneth M; Hajjar Roger JJACC. Cardiovascular imaging (2018), 11 (2 Pt 2), 333-335 ISSN:.There is no expanded citation for this reference.241White, F. J.; Kalivas, P. W. Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend. 1998, 51, 141– 153, DOI: 10.1016/S0376-8716(98)00072-6[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXks1Olsbo%253D&md5=46663898a8b5b199218728fb800028c6Neuroadaptations involved in amphetamine and cocaine addictionWhite, Francis J.; Kalivas, Peter W.Drug and Alcohol Dependence (1998), 51 (1,2), 141-153CODEN: DADEDV; ISSN:0376-8716. (Elsevier Science Ireland Ltd.)A review with 149 refs., describing mol. interactions of cocaine and amphetamine with dopamine transporters, acute effects of psychostimulants, repeated administration of psychostimulants, and neuroadaptation in glutamate transmission.242Fowler, J. S.; Volkow, N. D.; Wolf, A. P.; Dewey, S. L.; Schlyer, D. J.; MacGregor, R. R.; Hitzemann, R.; Logan, J.; Bendriem, B.; Gatley, S. J.; Christman, D. Mapping cocaine binding sites in human and baboon brain in vivo. Synapse 1989, 4, 371– 377, DOI: 10.1002/syn.890040412[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXptFKhtw%253D%253D&md5=b5adb05a934b154e8fd7511579eaca84Mapping cocaine binding sites in human and baboon brain in vivoFowler, Joanna S.; Volkow, Nora D.; Wolf, Alfred P.; Dewey, Stephen L.; Schlyer, David J.; Macgregor, Robert R.; Hitzemann, Robert; Logan, Jean; Bendriem, Bernard; et al.Synapse (New York, NY, United States) (1989), 4 (4), 371-7CODEN: SYNAET; ISSN:0887-4476.The direct measurements of cocaine binding in human and baboon brain were made by using positron tomog. (PET) and tracer doses of [N-11C-methyl]-(-)-cocaine ([11C]cocaine). Cocaine's binding and release from brain were rapid with the highest regional uptake of 11C occurring in the corpus striatum at 4-10 min after i.v. injection of labeled cocaine. This was followed by a clearance to half the peak value at 25 min with the overall time course paralleling the peak behavioral activation and subsequent decline after i.v. cocaine administration. Blockade of the dopamine reuptake sites with nomifensine reduced the striatal but not the cerebellar uptake of [11C]cocaine in baboons indicating that cocaine binding is assocd. with the dopamine reuptake site in the corpus striatum. While cocaine is rapidly metabolized in both human and baboon, the profile of labeled metabolites is different, with baboon plasma contg. significant amts. of labeled CO2 but not human plasma. These data showed the feasibility of using [11C]cocaine and PET to map binding sites for cocaine in human brain, to study its kinetics and binding mechanism.243Wang, G.-J.; Volkow, N. D.; Fowler, J. S.; Fischman, M.; Foltin, R.; Abumrad, N. N.; Logan, J.; Pappas, N. R. Cocaine abusers do not show loss of dopamine transporters with age. Life Sci. 1997, 61, 1059– 1065, DOI: 10.1016/S0024-3205(97)00614-0[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlsVCkt7g%253D&md5=e55b0005fee05a19f9293d54d490a7feCocaine abusers do not show loss of dopamine transporters with ageWang, Gene-Jack; Volkow, Nora D.; Fowler, Joanna S.; Fischman, Marian; Foltin, Richard; Abumrad, Naji N.; Logan, Jean; Pappas, Naomi R.Life Sciences (1997), 61 (11), 1059-1065CODEN: LIFSAK; ISSN:0024-3205. (Elsevier)Cocaine blocks dopamine transporters (DAT) and this effect is crucial to its reinforcing properties. To assess the effects of chronic cocaine on DAT we evaluated 20 current cocaine abusers and 20 age matched controls using PET and [C-11]cocaine as a DAT ligand. Though there were no differences in DAT availability between groups, current cocaine abusers (and 12 detoxified cocaine abusers studied previously) did not show the typical age-related decline in DAT seen in controls. Though further studies are required to rule out sampling effects and to control for confounding variables (i.e. smoking), one could speculate that chronic DAT blockade by cocaine has a protective effect on the loss of DAT with age.244Volkow, N. Cocaine uptake is decreased in the brain of detoxified cocaine abusers. Neuropsychopharmacology 1996, 14, 159– 168, DOI: 10.1016/0893-133X(95)00073-M[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XitVGrtbo%253D&md5=b12ff4f1c8122b03f41157e883f849faCocaine uptake is decreased in the brain of detoxified cocaine abusersVolkow, N. D.; Wang, G. -J.; Fowler, J. S.; Logan, J.; Hitzemann, R.; Gatley, S. J.; MacGregor, R. R.; Wolf, A. P.Neuropsychopharmacology (1996), 14 (3), 159-68CODEN: NEROEW; ISSN:0893-133X. (Elsevier)Binding of [11C]cocaine in brain was measured with positron emission tomog. in 12 detoxified cocaine abusers and in 20 controls to evaluate if there were changes in cocaine binding and in dopamine (DA) transporter availability assocd. with chronic cocaine use. Nine controls and 10 cocaine abusers had an addnl. scan with [18F]N-methylspiroperidol to measure dopamine D2 receptors. Cocaine abusers had significantly lower uptake of [11C]cocaine in brain (6.2% dose/mL tissues) than controls (7.7%). The distribution vols. (DV) for [11C]cocaine were reduced in basal ganglia (BG), cortex, thalamus, and cerebellum (CB) of cocaine abusers. However there were no differences in the ratio of the DV in BG to that in CB, which is an est. of DA transporter availability. Values for DA D2 receptor availability were decreased in cocaine abusers and did not correlate with ests. of dopamine transporter availability. In summary, detoxified cocaine abusers showed decreased uptake of cocaine in brain but did not show changes in DA transporter availability.245Volkow, N. D.; Fowler, J. S.; Wang, G.-J. Positron emission tomography and single-photon emission computed tomography in substance abuse research. Semin. Nucl. Med. 2003, 33, 114– 128, DOI: 10.1053/snuc.2003.127300[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s3jsVantA%253D%253D&md5=18cc4941c3f3e129f551705c518d29bcPositron emission tomography and single-photon emission computed tomography in substance abuse researchVolkow Nora D; Fowler Joanna S; Wang Gene-JackSeminars in nuclear medicine (2003), 33 (2), 114-28 ISSN:0001-2998.Many advances in the conceptualization of addiction as a disease of the brain have come from the application of imaging technologies directly in the human drug abuser. New knowledge has been driven by advances in radiotracer design and chemistry and positron emission tomography (PET) and single-photon emission computed tomography (SPECT) instrumentation and the integration of these scientific tools with the tools of biochemistry, pharmacology, and medicine. This topic cuts across the medical specialties of neurology, psychiatry, oncology, and cardiology because of the high medical, social, and economic toll that drugs of abuse, including the legal drugs, cigarettes and alcohol, take on society. This article highlights recent advances in the use of PET and SPECT imaging to measure the pharmacokinetic and pharmacodynamic effects of drugs of abuse on the human brain.246Ginovart, N. PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington’s disease. Brain. 1997, 120, 503– 514, DOI: 10.1093/brain/120.3.503[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3ntFWisg%253D%253D&md5=b2bfd52318bc0781af3c4a05b9a3a7f0PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's diseaseGinovart N; Lundin A; Farde L; Halldin C; Backman L; Swahn C G; Pauli S; Sedvall GBrain : a journal of neurology (1997), 120 ( Pt 3) (), 503-14 ISSN:0006-8950.PET and: markers for the pre- and postsynaptic neurons were used to study the dopamine system in vivo in Huntington's disease. The radioligands used were [11C]SCH 23390 for D1-receptors, [11C]raclopride for D2-receptors and [11C]beta-CIT for dopamine transporters. Five patients with Huntington's disease and five matched controls were recruited. Brain anatomy was examined by MRI. The findings in patients were as follows. Postsynaptic D1- and D2-receptor densities were similarly reduced in the striatum. A reduction in D1-receptor density was shown in the temporal cortex; it draws attention to the cortical degeneration in relation to the cognitive deficits observed in Huntington's disease. The reduction of D1- and D2-receptor binding potentials in the striatum correlated significantly with increasing duration of illness. The correlation between the duration of illness and decline of D1- and D2-receptors make these receptors valuable as quantitative markers for the Huntington's disease degenerative process. Besides postsynaptic changes, a significant 50% decrease of [11C]beta-CIT binding to the dopamine transporter was found in the striatum. A reduced striatal blood flow in Huntington's disease cannot be excluded and could account for a small part of the decrease in [11C]beta-CIT binding. We suggest that the finding reflects a loss of presynaptic terminals or a reduced expression of dopamine transporter in the nigrostriatal dopaminergic system in Huntington's disease.247Halldin, C.; Erixon-Lindroth, N.; Pauli, S.; Chou, Y.-H.; Okubo, Y.; Karlsson, P.; Lundkvist, C.; Olsson, H.; Guilloteau, D.; Emond, P.; Farde, L. [(11)C]PE2I: A highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 1220– 1230, DOI: 10.1007/s00259-003-1212-3[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXms12hurk%253D&md5=ad443ce95c326ce909c87aaf36ea0b6d[11C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brainHalldin, Christer; Erixon-Lindroth, Nina; Pauli, Stefan; Chou, Yuan-Hwa; Okubo, Yoshiro; Karlsson, Per; Lundkvist, Camilla; Olsson, Hans; Guilloteau, Denis; Emond, Patrick; Farde, LarsEuropean Journal of Nuclear Medicine and Molecular Imaging (2003), 30 (9), 1220-1230CODEN: EJNMA6; ISSN:1619-7070. (Springer-Verlag)The aim of this study was to explore the potential of a new selective dopamine transporter (DAT) compd. as a radioligand for positron emission tomog. (PET) examn. of DAT in the human brain. The high affinity DAT compd. N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane (PE2I) was radiolabeled by the O-methylation approach and the binding was characterized by PET in cynomolgus monkeys and a healthy man. Metabolite levels in plasma were measured by gradient high-performance liq. chromatog. O-methylation of the corresponding free acid precursor with [11C]methyl triflate gave high radiochem. yield (80%) and specific radioactivity (55 GBq/μmol). [11C]PE2I binding in cynomolgus monkeys was nine times higher in the striatum than in the cerebellum at peak equil., which appeared 55-65 min after injection. Displacement and pretreatment measurements using unlabeled β-CIT, GBR 12909, cocaine, citalopram and maprotiline confirmed that [11C]PE2I binds selectively to DAT. In a preliminary study in one human subject the radioactivity ratios of the striatum and substantia nigra to the cerebellum were 10 and 1.8, resp., at peak equil., which appeared at 40-50 min and 20 min, resp., after injection. The fraction of the total radioactivity in monkey and human plasma representing unchanged [11C]PE2I was 15-20% at 40 min after injection. The present characterization of binding in monkey and man suggests that [11C]PE2I is a suitable PET radioligand for quant. regional examn. of DAT in man.248Varrone, A.; Tóth, M.; Steiger, C.; Takano, A.; Guilloteau, D.; Ichise, M.; Gulyás, B.; Halldin, C. Kinetic analysis and quantification of the dopamine transporter in the nonhuman primate brain with 11C-PE2I and 18F-FE-PE2I. J. Nucl. Med. 2011, 52, 132– 139, DOI: 10.2967/jnumed.110.077651[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtleisLo%253D&md5=6c474e7036add7329c257c89f09b763cKinetic analysis and quantification of the dopamine transporter in the nonhuman primate brain with 11C-PE2I and 18F-FE-PE2IVarrone, Andrea; Toth, Miklos; Steiger, Carsten; Takano, Akihiro; Guilloteau, Denis; Ichise, Masanori; Gulyas, Balazs; Halldin, ChristerJournal of Nuclear Medicine (2011), 52 (1), 132-139CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl)nortropane (18F-FE-PE2I) is a novel radioligand for dopamine transporter (DAT) PET. As compared with 11C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane (11C-PE2I), 18F-FE-PE2I shows faster kinetics and more favorable metab., with less prodn. of a radiometabolite with intermediate lipophilicity (M1), which-in the case of 11C-PE2I-has been shown to enter the rat brain. In this study, we compared DAT quantification with 11C-PE2I and 18F-FE-PE2I in nonhuman primates, using kinetic and graphical anal. with the input function of both the parent and the radiometabolite, to assess the potential contribution of the radiometabolite. Methods: Three rhesus monkeys were examd. with 11C-PE2I and 18F-FE-PE2I using the HRRT system. Arterial input functions of the parent and radiometabolite M1 were measured. Kinetic and graphical analyses were applied using either the parent input (methods 1 and 3) or the parent plus radiometabolite input (methods 2 and 4). Outcome measures were distribution vols. (VT and VND), specific-to-nondisplaceable tissue radioactivity ratio at equil. (BPND; parent input), and specific-to-nondisplaceable tissue radioactivity ratio at equil. in the presence of metabolites (RT; parent plus radiometabolite input). Results: 11C-PE2I showed higher distribution vols. than 18F-FE-PE2I calcd. with methods 1 and 3 (striatal VT, ∼300%; VND in cerebellum, ∼30%). With methods 2 and 4, VT in the striatum was approx. 60% higher in the case of 11C-PE2I, whereas no difference in VND was found in the cerebellum. For each radioligand, BPND estd. with methods 1 and 3 tended to be higher than RT estd. with methods 2 and 4. However, the bias of BPND, compared with RT, was much larger for 11C-PE2I (40%-60% in the caudate and putamen) than for 18F-FE-PE2I (<10% in the caudate and putamen). Conclusion: The direct comparison between the radioligands confirmed that 18F-FE-PE2I shows faster kinetics and more favorable metab. than 11C-PE2I. The kinetic and graphical analyses with the input function of the parent and radiometabolite showed that the bias in BPND was much lower for 18F-FE-PE2I than for 11C-PE2I and suggested that the lower prodn. of the radiometabolite M1 would make 18F-FE-PE2I more suitable for the DAT quantification. Further studies in humans are necessary to confirm these findings.249Jonasson, M.; Appel, L.; Danfors, T.; Nyholm, D.; Askmark, H.; Frick, A.; Engman, J.; Furmark, T.; Sörensen, J.; Lubberink, M. Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction. Am. J. Nucl. Med. Mol. Imaging 2017, 7, 263– 274[PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmvVSjt7c%253D&md5=960adbbcc5e146f5a0f079a835f2c79dDevelopment of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extractionJonasson, My; Appel, Lieuwe; Danfors, Torsten; Nyholm, Dag; Askmark, Haakan; Frick, Andreas; Engman, Jonas; Furmark, Tomas; Soerensen, Jens; Lubberink, MarkAmerican Journal of Nuclear Medicine and Molecular Imaging (2017), 7 (6), 263-275CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)[11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clin. application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum ref. region defined on a co-registered MRI, as well as a supervised cluster anal. (SVCA)-based ref. Initial 20, 30 and 40 min of the scans were extd. and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based ref. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extn. of a ref. region. These outcomes will support routine applications of [11C]PE2I PET in clin. settings.250Appel, L.; Jonasson, M.; Danfors, T.; Nyholm, D.; Askmark, H.; Lubberink, M.; Sorensen, J. Use of 11C-PE2I PET in differential diagnosis of parkinsonian disorders. J. Nucl. Med. 2015, 56, 234– 242, DOI: 10.2967/jnumed.114.148619[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislOgs74%253D&md5=30000cf5b125758031db5a97314fda6eUse of 11C-PE2I PET in differential diagnosis of parkinsonian disordersAppel, Lieuwe; Jonasson, My; Danfors, Torsten; Nyholm, Dag; Askmark, Haakan; Lubberink, Mark; Soerensen, JensJournal of Nuclear Medicine (2015), 56 (2), 234-242/1-234-242/9, 9 pp.CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clin. diagnosis. A dual examn. using 123I-FP-CIT (123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane, or 123I-ioflupane) SPECT and 18F-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, resp. Parametric images based on a single, dynamic 11C-PE2I (N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methyl-phenyl)nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R1]) at voxel level. This study aimed to evaluate the validity of 11C-PE2I PET against the dual-modality approach using 123I-FP-CIT SPECT and 18F-FDG PET. Methods: Sixteen patients with parkinsonian disorders had a dual examn. with 18F-FDG PET and 123I-FP-CIT SPECT following clin. routines and addnl. an exptl. 11C-PE2I PET scan. Parametric BPND and R1 images were generated using receptor parametric mapping with the cerebellum as a ref. T1-weighted MR imaging was used for automated definition of vols. of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examd. using VOIs across the brain. BPND and R1 values were compared with normalized 123I-FP-CIT and 18F-FDG uptake values, resp., using Pearson correlations and regression analyses. In addn., 2 masked interpreters evaluated the images visually, in both the routine and the exptl. datasets, for comparison of patient diagnoses. Results: Parametric 11C-PE2I BPND and R1 images showed high consistency with 123I-FP-CIT SPECT and 18F-FDG PET images. Correlations between 11C-PE2I BPND and 123I-FP-CIT uptake ratios were 0.97 and 0.76 in the putamen and caudate nucleus, resp. Regional 11C-PE2I R1 values were moderately to highly correlated with normalized 18F-FDG values (range, 0.61-0.94). Visual assessment of DAT availability showed a high consistency between 11C-PE2I BPND and 123I-FP-CIT images, whereas the consistency was somewhat lower for appraisal of overall brain functional activity using 123I-FP-CIT and 18F-FDG images. Substantial differences were found between clin. diagnosis and both neuroimaging diagnoses. Conclusion: A single, dynamic 11C-PE2I PET investigation is a powerful alternative to a dual examn. with (123)I-FP-CIT SPECT and (18)F-FDG PET for differential diagnosis of parkinsonian disorders. A large-scale patient study is, however, needed to further investigate distinct pathol. patterns in overall brain functional activity for various parkinsonian disorders.251Fazio, P.; Svenningsson, P.; Forsberg, A.; Jönsson, E. G.; Amini, N.; Nakao, R.; Nag, S.; Halldin, C.; Farde, L.; Varrone, A. Quantitative analysis of 18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4’-methyl-phenyl) nortropane binding to the dopamine transporter in Parkinson disease. J. Nucl. Med. 2015, 56, 714– 720, DOI: 10.2967/jnumed.114.152421[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFakt7%252FF&md5=61a35862f29aea0314570cd128ef8677Quantitative analysis of 18F-(E)-N-(3-iodoprop-2-enyl)-2β-Carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane binding to the dopamine transporter in Parkinson diseaseFazio, Patrik; Svenningsson, Per; Forsberg, Anton; Joensson, Erik G.; Amini, Nahid; Nakao, Ryuji; Nag, Sangram; Halldin, Christer; Farde, Lars; Varrone, AndreaJournal of Nuclear Medicine (2015), 56 (5), 714-720CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane (18F-FE-PE2I) is a recently developed radioligand for the in vivo quantification of the dopamine transporter (DAT) in the striatum and substantia nigra (SN). The aim of this study was to examine the suitability of 18F-FE-PE2I as a tool for imaging the nigrostriatal pathway in Parkinson disease (PD) with PET. Methods: Ten PD patients (9 men and 1 woman; mean age ± SD, 60 ± 9 y; Hoehn and Yahr, 1-2; Unified Parkinson Disease Rating Scale motor, 18.9 ± 6.7) and 10 controls (9 men and 1 woman; mean age ± SD, 60 ± 7 y) were included. PET measurements with 18F-FE-PE2I were conducted for 93 min using the High-Resoln. Research Tomograph. Venous blood was drawn to compare protein binding, parent fraction, and radiometabolite compn. in PD patients and controls. Regions of interest for the caudate, putamen, ventral striatum, SN, and cerebellum were drawn on coregistered MR images. The outcome measure was the binding potential (BPND) estd. with the simplified ref. tissue model and the Logan graphical anal., using the cerebellum as a ref. region. Time stability of BPND was examd. to define the shortest acquisition protocol for quant. studies. The wavelet-aided parametric imaging method was used to obtain high-resoln. BPND images to compare DAT availability in the striatum and SN in PD patients and control subjects. Group differences were assessed with the unpaired t test (P < 0.05). Results: Parent, radiometabolite fractions, plasma concn., and cerebellar uptake of 18F-FE-PE2I did not differ significantly between PD patients and controls. Stable ests. of BPND (<8% of the 93-min value) were obtained with the simplified ref. tissue model using approx. 66 min of data. BPND values in PD patients were significantly lower than those in controls (P < 0.05) in the caudate (2.54 ± 0.79 vs. 3.68 ± 0.56), putamen (1.39 ± 1.04 vs. 4.41 ± 0.54), ventral striatum (2.26 ± 0.93 vs. 3.30 ± 0.46), and SN (0.46 ± 0.20 vs. 0.68 ± 0.15). Conclusion: 18F-FE-PE2I is clearly a suitable radioligand for DAT quantification and imaging of the nigrostriatal pathway in PD. Similar metab. in controls and PD patients, suitability of the cerebellum as a ref. region, and accuracy of quantification using approx. 66 min of PET data are advantages for noninvasive and simplified imaging protocols for PD studies. Finally, DAT loss in PD can be measured in both the striatum and the SN, supporting the utility of 18F-FE-PE2I as an imaging tool of the nigrostriatal pathway.252Frey, K. A.; Koeppe, R. A.; Kilbourn, M. R.; Vander Borght, T. M.; Albin, R. L.; Gilman, S.; Kuhl, D. E. Presynaptic monoaminergic vesicles in Parkinson’s disease and normal aging. Ann. Neurol. 1996, 40, 873– 884, DOI: 10.1002/ana.410400609[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7lvFGktA%253D%253D&md5=f1a19f1066caaeb4bbd9988575201ef6Presynaptic monoaminergic vesicles in Parkinson's disease and normal agingFrey K A; Koeppe R A; Kilbourn M R; Vander Borght T M; Albin R L; Gilman S; Kuhl D EAnnals of neurology (1996), 40 (6), 873-84 ISSN:0364-5134.We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [11C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug- or lesion-compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood-brain [11C]DTBZ transport (K1) and VMAT2 binding site density (tissue-to-plasma DTBZ distribution volume, DV) from the cerebral and plasma DTBZ time courses after intravenous tracer injection. In controls, we found reductions of putamen DTBZ DVwith advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (-61%) and in the caudate nucleus (-43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [11C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.253Frey, K. A.; Koeppe, R. A.; Kilbourn, M. R. Imaging the vesicular monoamine transporter. Adv. Neurol. 2001, 86, 237– 247[PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjvFKhsrY%253D&md5=4847b93eeb0a633fb996e1970f2a4b51Imaging the vesicular monoamine transporterFrey, Kirk A.; Koeppe, Robert A.; Kilbourn, Michael R.Advances in Neurology (2001), 86 (Parkinson's Disease), 237-247CODEN: ADNRA3; ISSN:0091-3952. (Lippincott-Raven Publishers)A review with 79 refs. Parkinson's disease (PD), proposed formally as a neurol. syndrome in 1817 by James Parkinson, remains today the most common neurodegenerative disease of movement and the second most common neurodegenerative disorder after Alzheimer's disease. The cardinal symptoms of PD affect voluntary movement, consisting of bradykinesia and rigidity together with a resting tremor. Although detailed population-based data are lacking, ests. of its prevalence in the Unites States run between 250,000 and in excess of 500,000 cases, with an annual incidence of 14/100,000. The incidence of PD increases with age in 'adulthood, peaking between ages 55 and 60. The no. of PD patients in the United States is projected to increase over fourfold in the next half-century on the basis of an increasing aged population. In the ongoing search for neuroprotective, disease-modifying PD therapies, availability of an objective, quant. marker of nigrostriatal-damage will be essential to assess outcome and endpoints.254Bohnen, N. I.; Koeppe, R. A.; Meyer, P.; Ficaro, E.; Wernette, K.; Kilbourn, M. R.; Kuhl, D. E.; Frey, K. A.; Albin, R. L. Decreased striatal monoaminergic terminals in Huntington disease. Neurology 2000, 54, 1753– 1759, DOI: 10.1212/WNL.54.9.1753[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c3msVCntA%253D%253D&md5=ec7bc5ed0d2fa21714147924a4567276Decreased striatal monoaminergic terminals in Huntington diseaseBohnen N I; Koeppe R A; Meyer P; Ficaro E; Wernette K; Kilbourn M R; Kuhl D E; Frey K A; Albin R LNeurology (2000), 54 (9), 1753-9 ISSN:0028-3878.OBJECTIVE: To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). BACKGROUND: Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. METHODS: Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. RESULTS: The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.255Shi, X.; Zhang, Y.; Xu, S.; Kung, H. F.; Qiao, H.; Jiang, L.; Zhu, L.; Guo, Q.; Yi, C.; Luo, G.; Wu, L.; Pei, Z.; Wang, J.; Zhang, X.; Chen, L. Decreased striatal vesicular monoamine transporter type 2 correlates with the nonmotor symptoms in Parkinson disease. Clinical Nuclear Medicine. 2019, 44, 707– 713, DOI: 10.1097/RLU.0000000000002664[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M3ntlCkug%253D%253D&md5=2a9ac0fb0766f85cc7ae44c43db91c0bDecreased Striatal Vesicular Monoamine Transporter Type 2 Correlates With the Nonmotor Symptoms in Parkinson DiseaseShi Xinchong; Yi Chang; Luo Ganhua; Zhang Xiangsong; Zhang Yan; Zhu Lin; Xu Shaohua; Jiang LuLu; Guo Qiyi; Wu Lei; Pei Zhong; Chen Ling; Kung Hank F; Qiao Hongwen; Wang JianClinical nuclear medicine (2019), 44 (9), 707-713 ISSN:.OBJECTIVE: Nonmotor symptoms (NMS) are critical players in the patients' quality of life in Parkinson disease (PD). Vesicular monoamine transporter type 2 (VMAT2) has been reported owing to a role in affecting dopamine neurons in the striatum. Therefore, this study set out to characterize the relationship between VMAT2 distribution in the striatum in relation to the NMS in PD. METHODS: Totally, 21 age-matched normal controls and 37 patients with PD in the moderate stages were included, followed by examination using F-DTBZ (F-AV133) PET/CT. The specific uptake ratio (SUR) of each striatal subregion was then determined with the occipital cortex as the reference background region. The overall NMSs of each individual patient were evaluated. Finally, the role of the striatal SURs in the clinical symptom scores were evaluated through the application of a Spearman correlation analysis as well as a multivariable stepwise regression analysis. RESULTS: Patients with PD, particularly those at a more advanced stage, exhibited a more pronounced reduction in SURs in the bilateral putamen and caudate nucleus (P < 0.05, vs healthy controls). Meanwhile, patients at more advanced PD stages were found to have significantly worse scores in NMS except cognitive function. The Spearman correlation analysis demonstrated that NMS scores, with the exception of cognition scores, were correlated with striatal SURs (P < 0.05). CONCLUSION: The key findings of the study identified a correlation between decreased striatal VMAT2 with a broad spectrum of NMS in patients with PD, highlighting the association between diminished dopamine supply and the development of NMS in PD.256Cho, S. S.; Christopher, L.; Koshimori, Y.; Li, C.; Lang, A. E.; Houle, S.; Strafella, A. P. Decreased pallidal vesicular monoamine transporter type 2 availability in Parkinson’s disease: The contribution of the nigropallidal pathway. Neurobiol. Dis. 2019, 124, 176– 182, DOI: 10.1016/j.nbd.2018.11.022[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlensLbO&md5=f0cc4962ad2e2c7d3f54f737f2701acdDecreased pallidal vesicular monoamine transporter type 2 availability in Parkinson's disease: The contribution of the nigropallidal pathwayCho, Sang Soo; Christopher, Leigh; Koshimori, Yuko; Li, Crystal; Lang, Anthony E.; Houle, Sylvain; Strafella, Antonio P.Neurobiology of Disease (2019), 124 (), 176-182CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)To date, the contribution of the nigropallidal pathway degeneration to Parkinson's disease (PD) motor symptoms has received little attention and is generally poorly understood in spite of solid evidence that the globus pallidus (GP) receives a dense neuronal projection from the substantia nigra. To explore the dopaminergic (DA) changes of the GP in PD, we measured the availability of vesicular monoamine transporter 2 (VMAT2) using [11C]DTBZ and positron emission tomog. in 30 PD patients and 12 controls. PD patients were classified in two groups based on severity of disease. VMAT2 redn. was found to be significant in the external GP (GPe) regardless of the disease stage, while the internal GP (GPi) showed redn. only in more severe patients. Pallidal VMAT2 binding correlated with dopaminergic changes in the striatum, with the GPe showing a stronger assocn. than GPi. Our findings showed DA terminals in the GPe and GPi may be differentially vulnerable in different stages of the disease, possibly playing a distinctive role in the development of motor complications with GPi DA deficiency contributing more to later-stage symptoms.257Lin, K.-J.; Weng, Y.-H.; Wey, S.-P.; Hsiao, I.-T.; Lu, C.-S.; Skovronsky, D.; Chang, H.-P.; Kung, M.-P.; Yen, T.-C. Whole-body biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): A novel vesicular monoamine transporter 2 imaging agent. J. Nucl. Med. 2010, 51, 1480– 1485, DOI: 10.2967/jnumed.110.078196[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1ejsLjM&md5=50db85e8ecfbb8824968523a88078a93Whole-body biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): a novel vesicular monoamine transporter 2 imaging agentLin, Kun-Ju; Weng, Yi-Hsin; Wey, Shiaw-Pyng; Hsiao, Ing-Tsung; Lu, Chin-Song; Skovronsky, Daniel; Chang, Hsiu-Ping; Kung, Mei-Ping; Yen, Tzu-ChenJournal of Nuclear Medicine (2010), 51 (9), 1480-1485CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-18F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7, 11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (18F-FP-(+)-dihydrotetrabenazine [DTBZ] or 18F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clin. use. 9 Healthy human subjects (mean age ± SD, 58.6 ± 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 ± 22.9 MBq of 18F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to det. the equiv. dose for individual organs. The radiotracer did not show any noticeable adverse effects for the 9 subjects examd. The radioactivity uptake in the brain was the highest at 7.5% ± 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 ± 23.8 μGy/MBq, was the pancreas. The ED equiv. and ED for 18F-AV-133 were 36.5 ± 2.8 and 27.8 ± 2.5 μSv/MBq, resp. These values are comparable to those reported for any other 18F-labeled radiopharmaceutical. 18F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans.258Lin, S.-C.; Lin, K.-J.; Hsiao, I.-T.; Hsieh, C.-J.; Lin, W.-Y.; Lu, C.-S.; Wey, S.-P.; Yen, T.-C.; Kung, M.-P.; Weng, Y.-H. In vivo detection of monoaminergic degeneration in early Parkinson disease by 18F-9-fluoropropyl-(+)-dihydrotetrabenzazine PET. J. Nucl. Med. 2014, 55, 73– 79, DOI: 10.2967/jnumed.113.121897[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlCktb0%253D&md5=c8ab5ea97ec3bcfa43803bb0debed2faIn vivo detection of monoaminergic degeneration in early Parkinson disease by 18F-9-fluoropropyl-(+)- dihydrotetrabenzazine PETLin, Shao-Cheng; Lin, Kun-Ju; Hsiao, Ing-Tsung; Hsieh, Chia-Ju; Lin, Wey-Yil; Lu, Chin-Song; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Kung, Mei-Ping; Weng, Yi-HsinJournal of Nuclear Medicine (2014), 55 (1), 73-79CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)PET with 18F-9-fluoropropyl-(+)-dihydrotetrabenzazine (18F-DTBZ), a novel radiotracer targeting vesicular monoamine transporter type 2 (VMAT2), has been proven as a useful imaging marker to measure dopaminergic integrity. Methods: The aim of this study was to evaluate the capability of 18F-DTBZ PET in detecting the monoaminergic degeneration in early Parkinson disease (PD) in vivo. Seventeen age-matched healthy subjects and 30 PD patients at early stage of disease (duration of disease ≤ 5 y) with mild and unilateral motor symptoms underwent 18F-DTBZ PET scans. The severity of disease, including Unified Parkinson Disease Rating Scale and modified Hoehn and Yahr Stage (mHY), were recorded at off-medication states. The standardized vols. of interest were applied to the spatial normalized image for quantification anal. The specific uptake ratios (SURs) were calcd. according to the formula (sp. vol.s-of-interest counts/occipital cortex counts) - 1. SUR measurements were summarized for each brain region. Results: The mean duration of disease in the PD group was 3.2 ± 2.1 y (range, 0.5-5 y). The mean mHY was 1.0 ± 0.1 (range, 1-1.5). The SURs of bilateral caudate, anterior putamen, posterior putamen, substantia nigra, and nucleus accumbens were significantly lower in PD patients than those of healthy subjects. The redn. of SURs was most severe in the contralateral (the brain regions that are located opposite to the symptomatic side) posterior putamen (-81%), followed by the ipsilateral posterior putamen (-67%). Receiver-operating-characteristic curve anal. showed that the SURs of the bilateral posterior putamen and contralateral anterior putamen had a sensitivity of 100% and specificity of 100% in differentiating PD patients from healthy subjects. Conclusion: 18F-DTBZ PET was as an excellent tool for the early diagnosis of PD. The obvious decline of 18F-DTBZ uptake in the ipsilateral (asymptomatic) striatum suggested that 18F-DTBZ PET might serve as an in vivo biomarker to detect the monoaminergic degeneration in the premotor phase of PD.259Siderowf, A.; Pontecorvo, M. J.; Shill, H. A.; Mintun, M. A.; Arora, A.; Joshi, A. D.; Lu, M.; Adler, C. H.; Galasko, D.; Liebsack, C.; Skovronsky, D. M.; Sabbagh, M. N. PET imaging of amyloid with florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer’s disease and lewy body disorders. BMC Neurol. 2014, 14, 79, DOI: 10.1186/1471-2377-14-79[Crossref], [PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs12hu73I&md5=2ddbc39cbf60e79d484438a86411ac88PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer's disease and Lewy body disordersSiderowf, Andrew; Pontecorvo, Michael J.; Shill, Holly A.; Mintun, Mark A.; Arora, Anupa; Joshi, Abhinay D.; Lu, Ming; Adler, Charles H.; Galasko, Douglas; Liebsack, Carolyn; Skovronsky, Daniel M.; Sabbagh, Marwan N.BMC Neurology (2014), 14 (), 79/1-79/9, 9CODEN: BNMEC8; ISSN:1471-2377. (BioMed Central Ltd.)Background: Biomarkers based on the underlying pathol. of Alzheimer's disease AD and Dementia with Lewy Bodies DLB have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson's disease PD using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 florbenazine, a marker for vesicular monamine type 2 transporters VMAT2. Methods: Patients with DLB and AD, Parkinson's disease PD and healthy controls HC were recruited for this study. On sep. days, subjects received i.v. injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 d. were assessed quant. and by binary clin. interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathol. AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding and correlated with measures of cognition and parkinsonism. Results: 11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group n = 21 compared to the PD/HC groups n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006. VMAT2 d. was significantly lower in the PD/DLB group n = 16 compared to the AD/ HC group n = 15; 1.83 vs. 2.97; p < 0.0001. Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding r = 0.73; p = 0.011. Conclusions: The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathol.260Lin, K.-J.; Weng, Y.-H.; Hsieh, C.-J.; Lin, W.-Y.; Wey, S.-P.; Kung, M.-P.; Yen, T.-C.; Lu, C.-S.; Hsiao, I.-T. Brain imaging of vesicular monoamine transporter type 2 in healthy aging subjects by 18F-FP-(+)-DTBZ PET. PLoS One 2013, 8, e75952 DOI: 10.1371/journal.pone.0075952[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFOnur%252FK&md5=69c5d3017ba1d87098ba96ee7422d7ecBrain imaging of vesicular monoamine transporter type 2 in healthy aging subjects by 18F-FP-(+)-DTBZ PETLin, Kun-Ju; Weng, Yi-Hsin; Hsieh, Chia-Ju; Lin, Wey-Yil; Wey, Shiaw-Pyng; Kung, Mei-Ping; Yen, Tzu-Chen; Lu, Chin-Song; Hsiao, Ing-TsungPLoS One (2013), 8 (9), e75952CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)18F-FP-(+)-DTBZ is a novel PET radiotracer targeting vesicular monoamine transporter type 2 (VMAT2). The goal was to explore the image features in normal human brains with 18F-FP-(+)-DTBZ as a ref. of mol. landmark for clin. diagnosis in Parkinson's disease (PD) and related disorders. Materials and Methods: A total of 22 healthy subjects (59.3 ± 6.0 years old) including 7 men and 15 women were recruited for MRI and 18F-FP-(+)-DTBZ PET scans. A total no. of 55 brain VOIs were selected for quantitation anal. The regional specific uptake ratio (SUR) was calcd. with occipital as ref. from MRI-based spatially normalized 18F-FP-(+)-DTBZ images. Regional percentage SUR to that of anterior putamen was calcd. Av. SUR images were displayed in 2D and 3D space to illustrate the image patterns. The correlation between age and regional VMAT2 uptake was also examd. Results: Visual assessment showed sym. uptake of 18F-FP-(+)-DTBZ and obviously highest in striatum, followed by nucleus accumbens, hypothalamus, substantia nigra, and raphe nuclei. Quantification anal. revealed striatal VMAT2 d. of anterior putamen > posterior putamen > caudate nucleus. Other subcortical regions were with moderate VMAT2 distribution (6∼51 % SUR of anterior putamen), while slightly lower VMAT2 was obsd. in cerebellum (10.60% SUR) and much lower in neocortex (<5% SUR). No significant correlation of SUR to age was found in subcortical regions. Conclusion: Using 18F-FP-(+)-DTBZ PET, we showed the 2D and 3D imaging features of the VMAT2 distribution in vivo in healthy aging brains. The in vivo imaging characteristics of VMAT2 is consistent with the expression of VMAT2 in a recent autopsy study. Therefore, 3D visualization and higher image quality of 18F-FP-(+)-DTBZ PET imaging might potentially be a powerful biomarker in detecting VMAT2 distribution of subcortical regions, and for Parkinson's disease and related neuropsychiatric disorders involving related monoaminergic systems.261Wu, X.; Zhou, X.; Zhang, S.; Zhang, Y.; Deng, A.; Han, J.; Zhu, L.; Kung, H. F.; Qiao, J. Brain uptake of a non-radioactive pseudo-carrier and its effect on the biodistribution of [18F]AV-133 in mouse brain. Nucl. Med. Biol. 2015, 42, 630– 636, DOI: 10.1016/j.nucmedbio.2015.03.009[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmvFaqtrk%253D&md5=c0a6295f32186fc2a61f8cafdbd25f19Brain uptake of a non-radioactive pseudo-carrier and its effect on the biodistribution of [18 F]AV-133 in mouse brainWu, Xianying; Zhou, Xue; Zhang, Shuxian; Zhang, Yan; Deng, Aifang; Han, Jie; Zhu, Lin; Kung, Hank F.; Qiao, JinpingNuclear Medicine and Biology (2015), 42 (7), 630-636CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)9-[18 F]Fluoropropyl-(+)-dihydrotetrabenazine ([18 F]AV-133) is a new PET imaging agent targeting vesicular monoamine transporter type II (VMAT2). To shorten the prepn. of [18 F]AV-133 and to make it more widely available, a simple and rapid purifn. method using solid-phase extn. (SPE) instead of high-pressure liq. chromatog. (HPLC) was developed. The SPE method produced doses contg. the non-radioactive pseudo-carrier 9-hydroxypropyl-(+)-dihydrotetrabenazine (AV-149). The objectives of this study were to evaluate the brain uptake of AV-149 by UPLC-MS/MS and its effect on the biodistribution of [18 F]AV-133 in the brains of mice. The mice were injected with a bolus including [18 F]AV-133 and different doses of AV-149. Brain tissue and blood samples were harvested. The effect of different amts. of AV-149 on [18 F]AV-133 was evaluated by quantifying the brain distribution of radiolabeled tracer [18 F]AV-133. The concns. of AV-149 in the brain and plasma were analyzed using a UPLC-MS/MS method. The concns. of AV-149 in the brain and plasma exhibited a good linear relationship with the doses. The receptor occupancy curve was fit, and the calcd. ED50 value was 8.165 mg/kg. The brain biodistribution and regional selectivity of [18 F]AV-133 had no obvious differences at AV-149 doses lower than 0.1 mg/kg. With increasing doses of AV-149, the brain biodistribution of [18 F]AV-133 changed significantly. The results are important to further support that the improved radiolabelling procedure of [18 F]AV-133 using an SPE method may be suitable for routine clin. application.262Huang, Z.-R.; Tsai, C.-L.; Huang, Y.-Y.; Shiue, C.-Y.; Tzen, K.-Y.; Yen, R.-F.; Hsin, L.-W. A novel potential positron emission tomography imaging agent for vesicular monoamine transporter type 2. PLoS One 2016, 11, e0161295 DOI: 10.1371/journal.pone.0161295[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFCisLw%253D&md5=f3bd19ae6fabfc5f9bb0cd9e7bb82d58A novel potential positron emission tomography imaging agent for vesicular monoamine transporter type 2Huang, Zih-Rou; Tsai, Chia-Ling; Huang, Ya-Yao; Shiue, Chyng-Yann; Tzen, Kai-Yuan; Yen, Ruoh-Fang; Hsin, Ling-WeiPLoS One (2016), 11 (9), e0161295/1-e0161295/11CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)In the early 1990s, 9-(+)-11C-dihydrotetrabenazine (9-(+)-11C-DTBZ) was shown to be a useful positron emission tomog. (PET) imaging agent for various neurodegenerative disorders. Here, we described the radiosynthesis and evaluation of the 9-(+)-11C-DTBZ analog, 10-(+)-11C-DTBZ, as a vesicular monoamine transporter 2 (VMAT2) imaging agent and compare it with 9-(+)-11C-DTBZ. 10-(+)-11C-DTBZ was obtained by 11C-MeI methylation with its 10 hydroxy precursor in the presence of 5 M NaOH. It had a slightly better av. radiochem. yield of 35.3 ± 3.6% (decay-cor. to end of synthesis (EOS)) than did 9-(+)-11C-DTBZ (30.5 ± 2.3%). MicroPET studies showed that 10-(+)-11C-DTBZ had a striatum-to-cerebellum ratio of 3.74 ± 0.21 at 40 min post-injection, while the ratio of 9-(+)-11C-DTBZ was 2.50 ± 0.33. This indicated that 10-(+)-11C-DTBZ has a higher specific uptake in VMAT2-rich brain regions, and 10-(+)-11C-DTBZ may be a potential VMAT2 radioligand. Our expt. is the first study of 10-(+)-11C-DTBZ to include dynamic brain distribution in rat brains.263Fowler, J. S.; Ding, Y.-S.; Volkow, N. D. Radiotracers for positron emission tomography imaging. Semin. Nucl. Med. 2003, 33, 14– 27, DOI: 10.1053/snuc.2003.127297[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252Fptlaksg%253D%253D&md5=eb47eff3d2a3e6b23507ddb9fa08eec8Radiotracers for positron emission tomography imagingFowler Joanna S; Ding Yu-Shin; Volkow Nora DSeminars in nuclear medicine (2003), 33 (1), 14-27 ISSN:0001-2998.Over the past 30 years, advances in radiotracer chemistry and positron emission tomography instrumentation have merged to make positron emission tomography a powerful scientific tool in the biomedical sciences. However, despite the increasing reliance of the biomedical sciences on imaging and the new needs for functional information created by the sequencing of the human genome, the development of new radiotracers with the specificity and kinetic characteristics for quantitative analysis in vivo remains a slow process. In this article, we focus on advances in the development of the radiotracers involved in neurotransmission, amino acid transport, protein synthesis, and DNA synthesis. We conclude with a brief section on newer radiotracers that image other molecular targets and conclude with a summary of some of the scientific and infrastructure needs that would expedite the development and introduction of new radiotracers into biomedical research and the practice of medicine.264Thompson, J. L.; Rosell, D. R.; Slifstein, M.; Girgis, R. R.; Xu, X.; Ehrlich, Y.; Kegeles, L. S.; Hazlett, E. A.; Abi-Dargham, A.; Siever, L. J. Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: A PET study with [11C]NNC112. Psychopharmacology. 2014, 231, 4231– 4240, DOI: 10.1007/s00213-014-3566-6[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntFGgsbo%253D&md5=e0f6076484ef954d653e07ca1c600198Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [11C]NNC112Thompson, Judy L.; Rosell, Daniel R.; Slifstein, Mark; Girgis, Ragy R.; Xu, Xiaoyan; Ehrlich, Yosefa; Kegeles, Lawrence S.; Hazlett, Erin A.; Abi-Dargham, Anissa; Siever, Larry J.Psychopharmacology (Heidelberg, Germany) (2014), 231 (21), 4231-4240CODEN: PSCHDL; ISSN:0033-3158. (Springer)Rationale: Schizotypal personality disorder (SPD) is assocd. with working memory (WM) impairments that are similar to those obsd. in schizophrenia. Imaging studies have suggested that schizophrenia is assocd. with alterations in dopamine D1 receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder. Objectives: The aim of this study was to characterize prefrontal D1 receptor availability and its relation to WM performance in SPD. Methods: We used positron emission tomog. (PET) and the radiotracer [11C]NNC112 with 18 unmedicated SPD and 21 healthy control participants; as an index of D1 receptor availability, binding potential (BP) measures (BPF, BPND, and BPP) were calcd. for prefrontal and striatal subregions. To assess WM, SPD participants completed the 2-back and Paced Auditory Serial Addn. Test (PASAT). Results: There were no significant group differences in PFC BP. BPF and BPP in the medial PFC were significantly neg. related to PASAT performance (rs = -0.551, p = .022 and rs = -0.488, p = .047, resp.), but BP was not related to 2-back performance. Conclusions: In contrast to what has been found in schizophrenia, SPD was not assocd. with significant alterations in prefrontal D1 receptor availability. Similar to previous schizophrenia findings, however, higher prefrontal D1 receptor availability was assocd. with poorer WM performance (as measured by the PASAT) in SPD. These findings suggest that schizophrenia and SPD may share a common pathophysiol. feature related to prefrontal dopamine functioning that contributes to WM dysfunction, but that in SPD, alterations in D1 may occur only in a subset of individuals and/or to an extent that is minor relative to what occurs in schizophrenia.265Abi-Dargham, A.; Xu, X.; Thompson, J. L.; Gil, R.; Kegeles, L. S.; Urban, N.; Narendran, R.; Hwang, D.-R.; Laruelle, M.; Slifstein, M. Increased prefrontal cortical D1 receptors in drug naïve patients with schizophrenia: A PET study with [11C]NNC112. J. Psychopharmacol. 2012, 26, 794– 805, DOI: 10.1177/0269881111409265[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1OksrrF&md5=4617272a99e78d7b806e4fc02d34473cIncreased prefrontal cortical D1 receptors in drug na.ovrddot.ive patients with schizophrenia: a PET study with [11C]NNC112Abi-Dargham, Anissa; Xu, Xiaoyan; Thompson, Judy L.; Gil, Roberto; Kegeles, Lawrence S.; Urban, Nina; Narendran, Raj; Hwang, Dah-Ren; Laruelle, Marc; Slifstein, MarkJournal of Psychopharmacology (London, United Kingdom) (2012), 26 (6), 794-805, 12 pp.CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)D1 receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomog. (PET) and a D1 radiotracer, [11C]NNC112, in drug na.ovrddot.ive (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, cor. for partial vol. effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial vol. effect cor. BPP measures were significantly higher in DN vs controls in cortical regions. No such increases were found in the DF vs. controls comparison. Furthermore, in the DF group, DF interval correlated pos. with cortical BPP. We conclude that upregulation of D1 receptors in schizophrenia is related to the illness itself and may be cor. and normalized by chronic antipsychotic treatment.266Poels, E. M. P.; Girgis, R. R.; Thompson, J. L.; Slifstein, M.; Abi-Dargham, A. In vivo binding of the dopamine-1 receptor PET Tracers [11C]NNC112 and [11C]SCH23390: A comparison study in individuals with schizophrenia. Psychopharmacology. 2013, 228, 167– 174, DOI: 10.1007/s00213-013-3026-8[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFOhurk%253D&md5=29c2a1212ff7abf1bcc44d34515125edIn vivo binding of the dopamine-1 receptor PET tracers [11C]NNC112 and [11C]SCH23390: a comparison study in individuals with schizophreniaPoels, Eline M. P.; Girgis, Ragy R.; Thompson, Judy L.; Slifstein, Mark; Abi-Dargham, AnissaPsychopharmacology (Heidelberg, Germany) (2013), 228 (1), 167-174CODEN: PSCHDL; ISSN:0033-3158. (Springer)Rationale: A deficit in dopamine-1 (D1) receptor function in the prefrontal cortex is suggested to play a role in the cognitive dysfunction obsd. in patients with schizophrenia. However, the results from positron emission tomog. imaging studies of D1 receptor levels in individuals with schizophrenia are mixed. Objectives: The aim of this investigation was to det. whether the in vivo characteristics of the different D1 receptor tracers used in previous reports, [11C]SCH23390 and [11C]NNC112, may have contributed to these discrepancies reported in the literature. Methods: Eight patients with schizophrenia and 12 healthy control subjects were scanned with both [11C]SCH23390 and [11C]NNC112. Results: [11C]SCH23390 and [11C]NNC112 binding potentials in both patients and control subjects were compared and no tracer by diagnosis interactions were obsd. Conclusions: The results of this study suggest that differences in the binding of [11C]SCH23390 and [11C]NNC112 obsd. in previous studies are not due to differences in the in vivo behavior of these tracers.267Plavén-Sigray, P.; Gustavsson, P.; Farde, L.; Borg, J.; Stenkrona, P.; Nyberg, L.; Bäckman, L.; Cervenka, S. Dopamine D1 receptor availability is related to social behavior: A positron emission tomography study. NeuroImage 2014, 102, 590– 595, DOI: 10.1016/j.neuroimage.2014.08.018[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSqsbnL&md5=833c660c0b51c173531cd44ea73fb8a5Dopamine D1 receptor availability is related to social behavior: A positron emission tomography studyPlaven-Sigray, Pontus; Gustavsson, Petter; Farde, Lars; Borg, Jacqueline; Stenkrona, Per; Nyberg, Lars; Baeckman, Lars; Cervenka, SimonNeuroImage (2014), 102 (Part_2), 590-595CODEN: NEIMEF; ISSN:1053-8119. (Elsevier Inc.)Dysfunctional interpersonal behavior is thought to underlie a wide spectrum of psychiatric disorders; however, the neurobiol. underpinnings of these behavioral disturbances are poorly understood. Previous mol. imaging studies have shown assocns. between striatal dopamine (DA) D2-receptor binding and interpersonal traits, such as social conformity. The objective of this study was to explore, for the first time, the role of DA D1-receptors (D1-Rs) in human interpersonal behavior.Twenty-three healthy subjects were examd. using positron emission tomog. and the radioligand [11C]SCH23390, yielding D1-R binding potential values. Striatal D1-R binding was related to personality scales selected to specifically assess one dimension of interpersonal behavior, namely a combination of affiliation and dominance (i.e., the Social Desirability, Verbal Trait Aggression and Phys. Trait Aggression scales from Swedish Universities Scales of Personality). An exploratory anal. was also performed for extrastriatal brain regions.D1-R binding potential values in the limbic striatum (r = .52; p = .015), associative striatum (r = .55; p = .009), and sensorimotor striatum (r = .67; p = .001) were pos. related to Social Desirability scores. D1-R binding potential in the limbic striatum (r = - .51; p = .019) was neg. assocd. with Phys. Trait Aggression scores. For extrastriatal regions, Social Desirability scores showed pos. correlations in the amygdala (r = .60; p = .006) and medial frontal cortex (r = .60; p = .004).This study provides further support for the role of DA function in the expression of disaffiliative and dominant traits. Specifically, D1-R availability may serve as a marker for interpersonal behavior in humans. Assocns. were demonstrated for the same dimension of interpersonal behavior as for D2-R, but in the opposite direction, suggesting that the two receptor subtypes are involved in the same behavioral processes, but with different functional roles.268Häggkvist, J.; Tóth, M.; Tari, L.; Varnäs, K.; Svedberg, M.; Forsberg, A.; Nag, S.; Dominguez, C.; Munoz-Sanjuan, I.; Bard, J.; Wityak, J.; Varrone, A.; Halldin, C.; Mrzljak, L. Longitudinal small-animal PET imaging of the zQ175 mouse model of Huntington disease shows in vivo changes of molecular targets in the striatum and cerebral cortex. J. Nucl. Med. 2017, 58, 617– 622, DOI: 10.2967/jnumed.116.180497[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmvVWrsb4%253D&md5=1d1913aa80597b5a04d7c5e803c19e00Longitudinal Small-Animal PET Imaging of the zQ175 mouse model of huntington disease shows in vivo changes of molecular targets in the striatum and cerebral cortexHaggkvist, Jenny; Toth, Miklos; Tari, Lenke; Varnas, Katarina; Svedberg, Marie; Forsberg, Anton; Nag, Sangram; Dominguez, Celia; Munoz-Sanjuan, Ignacio; Bard, Jonathan; Wityak, John; Varrone, Andrea; Halldin, Christer; Mrzljak, LadislavJournal of Nuclear Medicine (2017), 58 (4), 617-623CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Since the discovery of the HTT gene in 1993, numerous animal models have been developed to study the progression of Huntington disease (HD) and to evaluate potential new therapeutics. In the present study, we used small-animal PET to characterize the expression of mol. targets in the recently reported HD animal model, the zQ175 mouse model. Male heterozygous zQ175 (Htttm1Mfc/190JChdi, CHDI-81003003) and wild-type (WT, C57BL/6J) animals were imaged with the dopamine D2 receptor radioligand 11C-raclopride, the PDE10A radioligand 1F-MNI-659, the dopamine D receptor radioligand 11C-D1 receptor radioligand 11CNNC 112, and the 5-HT2A radioligand 11C-MDL 100907 at 6 and 9 mo of age. The outcome measure was the binding potential (BPND), using the cerebellum as the ref. region. Selected regions of interest were the striatum for all radioligands and addnl. the striatum, rostral cortex, caudal cortex, and hippocampus for 11C-NNC 112 and 11C-MDL 100907. At 6 mo of age, the BPND in the striatum was lower in zQ175 than WT animals by 40% for 11C-raclopride, by 52% for 1F-MNI-659, by 28% for 11C-NNC, and by 11% for 11C-MDL 100907. In the rostral cortex, D1 receptor binding was 22% lower in zQ175 than WT animals. We found an overall redn. in D1 and 5-HTA binding in the hippocampus of zQ175 compared with WT animals. The BPND of 11C-MDL 100907 in the caudal cortex was also lower in zQ175 WT animals. At 9 mo, there was a slight further redn. of D1, D2, and 5-HT2A BPND in the striatum, whereas PDE10A reached a plateau. Cortical markers were also slightly further decreased at 9 mo in zQ175 animals. Our study indicates a marked redn. of ligand binding to D1 and D2 and 5-HT2A receptors as well as loss of PDE10A enzyme in the striatum of zQ175 mice as compared with WT animals, in agreement with data obtained in clin. PET studies of patients with HD. The zQ175 mouse model recapitulates the expression pattern seen in humans with HD and may have value in further elucidating pathophysiol. events and therapeutic strategies.269Cannon, D. M.; Klaver, J. M.; Peck, S. A.; Rallis-Voak, D.; Erickson, K.; Drevets, W. C. Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [11C]NNC-112. Neuropsychopharmacology 2009, 34, 1277– 1287, DOI: 10.1038/npp.2008.194[Crossref], [PubMed], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtFentLo%253D&md5=89f711aa71340c074a40933d880702abDopamine Type-1 Receptor Binding in Major Depressive Disorder Assessed Using Positron Emission Tomography and [11C]NNC-112Cannon, Dara M.; Klaver, Jacqueline M.; Peck, Summer A.; Rallis-Voak, Denise; Erickson, Kristine; Drevets, Wayne C.Neuropsychopharmacology (2009), 34 (5), 1277-1287CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clin. and preclin. evidence from neuro-imaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D1 receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [11C]NNC-112, to selectively assess D1 receptor binding in extra-striatal and striatal regions in a more generalized sample of MDD subjects. The [11C]NNC-112 nondisplaceable binding potential (BPND) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest anal. The mean D1 receptor BPND was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D1 receptor BPND in this region correlated neg. with illness duration (r=-0.53; p=0.02), and the left-to-right BPND ratio correlated inversely with anhedonia ratings (r=-0.65, p=0.0040). The D1 receptor BPND was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbent area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F=7.33, p=0.01). These data extended a previous finding of decreased striatal D1 receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathol. changes have been reported in MDD. Finally, D1 receptor binding was asym. across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior.270Martinez, D.; Slifstein, M.; Narendran, R.; Foltin, R. W.; Broft, A.; Hwang, D.-R.; Perez, A.; Abi-Dargham, A.; Fischman, M. W.; Kleber, H. D.; Laruelle, M. Dopamine D1 receptors in cocaine dependence measured with PET and the choice to self-administer cocaine. Neuropsychopharmacology 2009, 34, 1774– 1782, DOI: 10.1038/npp.2008.235[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXls12quro%253D&md5=3d6b09e40dc8fd8fc7431f581f18ba28Dopamine D1 Receptors in Cocaine Dependence Measured with PET and the Choice to Self-Administer CocaineMartinez, Diana; Slifstein, Mark; Narendran, Rajesh; Foltin, Richard W.; Broft, Allegra; Hwang, Dah-Ren; Perez, Audrey; Abi-Dargham, Anissa; Fischman, Marian W.; Kleber, Herbert D.; Laruelle, MarcNeuropsychopharmacology (2009), 34 (7), 1774-1782CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)The goal of this study was to det. D1 receptor availability in human cocaine-dependent (CD) subjects and matched healthy controls (HCs). In addn., the CD subjects performed cocaine self-administration sessions in order to explore the assocn. between D1 receptor availability and cocaine-seeking behavior. Twenty-five CD subjects (40±4 years, 19M/6 F) and 23 matched HCs (38±4 years, 19M/4F) were scanned with PET and the radiotracer [11C]NNC 112. During the cocaine self-administration sessions, CD volunteers were given the choice to self-administer cocaine (0, 6, and 12 mg) or to receive a monetary voucher worth $5. D1 receptor availability was measured in the limbic, associative, and sensori-motor striatum in addn. to cortical brain regions. No difference in D1 receptor availability was seen between the two groups. A neg. assocn. was seen between D1 receptor BPND in the limbic striatum and the choice for the 6 mg dose of cocaine (r=-0.47, p=0.02, cor. for age). These results do not support the hypothesis that cocaine dependence is assocd. with a redn. in D1 receptor availability in the striatum. However, within the CD subjects, low D1 receptor availability in the ventral striatum was assocd. with the choice to self-administer cocaine, suggesting that low D1 receptor availability may be assocd. with an increased risk of relapse in cocaine dependence. Neuropsychopharmacol. (2009) 34, 1774-1782; doi:10.1038/npp.2008.235; published online 28 Jan. 2009.271Abi-Dargham, A.; Martinez, D.; Mawlawi, O.; Simpson, N.; Hwang, D.-R.; Slifstein, M.; Anjilvel, S.; Pidcock, J.; Guo, N.-N.; Lombardo, I.; Mann, J. J.; Van Heertum, R.; Foged, C.; Halldin, C.; Laruelle, M. Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: Validation and reproducibility. J. Cereb. Blood Flow Metab. 2000, 20, 225– 243, DOI: 10.1097/00004647-200002000-00003[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhs1altbY%253D&md5=313c891d53f8ad4f704e79155444362dMeasurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in Humans: validation and reproducibilityAbi-Dargham, Anissa; Martinez, Diana; Mawlawi, Osama; Simpson, Norman; Hwang, Dah-Ren; Slifstein, Mark; Anjilvel, Satish; Pidcock, Justine; Guo, Ning-Ning; Lombardo, Ilise; Mann, J. John; Van Heertum, Ronald; Foged, Christian; Halldin, Christer; Laruelle, MarcJournal of Cerebral Blood Flow and Metabolism (2000), 20 (2), 225-243CODEN: JCBMDN; ISSN:0271-678X. (Lippincott Williams & Wilkins)To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathol. requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomog. imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of anal. (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution vol., distribution vol. ratio, binding potential (BP), and specific-to-nonspecific equil. partition coeff. (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic anal. was excellent. Time-stability anal. indicated that 90 min of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic anal. was highly reliable, with intraclass correlation coeffs. (ICCs) of 0.90 (mean of 12 regions) and 0.84, resp. The reliability of these parameters derived by graphical anal. was lower, with ICCs of 0.72 and 0.58, resp. Noise anal. revealed a noise-dependent bias in the graphical but not the kinetic anal. In conclusion, kinetic anal. of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor d.272Sedvall, G.; Karlsson, P.; Lundin, A.; Anvret, M.; Suhara, T.; Halldin, C.; Farde, L. Dopamine D1 receptor number — A sensitive PET marker for early brain degeneration in Huntington’s disease. Eur. Arch Psychiatry Clin Neurosci. 1994, 243, 249– 255, DOI: 10.1007/BF02191583[Crossref], [PubMed], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2c3islWjsQ%253D%253D&md5=2906ab08f5bc894c069fec54d0427230Dopamine D1 receptor number--a sensitive PET marker for early brain degeneration in Huntington's diseaseSedvall G; Karlsson P; Lundin A; Anvret M; Suhara T; Halldin C; Farde LEuropean archives of psychiatry and clinical neuroscience (1994), 243 (5), 249-55 ISSN:0940-1334.D1-dopamine receptor binding in the brain was determined by positron emission tomography (PET) in five patients with Huntington's disease, in one asymptomatic gene carrier and in five control subjects. [11C] SCH 23390 was used as the radioligand. Brain morphology was recorded by MRI. The patients who all had a mild to moderate functional impairment showed an almost 50% reduction of putamen volume as well as D1-dopamine receptor density as compared to the controls. The total D1-dopamine receptor number in the putamen was reduced by 75% in the patient group. A similar reduction was found for the caudate nucleus. The asymptomatic gene carrier had volume and density values in the lower range of the control subjects. In the frontal neocortex there also tended to be a reduced D1-dopamine receptor binding in the symptomatic patients. The results indicate that [11C] SCH 23390 binding in combination with MRI can be used as a sensitive marker for early brain degeneration in Huntington's disease. This marker may be useful to monitor the pathophysiological effect of the disease gene and also to follow therapeutic interventions aiming at preventing the degenerative process.273Andrews, T. C.; Weeks, R. A.; Turjanski, N.; Gunn, R. N.; Watkins, L. H. A.; Sahakian, B.; Hodges, J. R.; Rosser, A. E.; Wood, N. W.; Brooks, D. J. Huntington’s disease progression: PET and clinical observations. Brain 1999, 122, 2353– 2363, DOI: 10.1093/brain/122.12.2353[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252FltVentA%253D%253D&md5=87e3e81e581455a6887207db17dee414Huntington's disease progression. PET and clinical observationsAndrews T C; Weeks R A; Turjanski N; Gunn R N; Watkins L H; Sahakian B; Hodges J R; Rosser A E; Wood N W; Brooks D JBrain : a journal of neurology (1999), 122 ( Pt 12) (), 2353-63 ISSN:0006-8950.Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months in nine asymptomatic adult Huntington's disease mutation carriers, four patients with symptomatic disease, seven mutation-negative controls and three subjects at risk for the disease. Eight of the nine asymptomatic Huntington's disease mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of striatal D2 binding of 4.0%. Only five of these eight, however, showed active progression, and they had a mean annual loss of D2 binding of 6.5%. All nine asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated active progression and they had a mean annual loss of 4.5%. Our four symptomatic Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly greater in the known mutation carriers than in the combined at-risk and gene-negative groups (P < 0.05). At follow-up PET all subjects were clinically assessed using the Unified Huntington's Disease Rating Scale. Scores for motor function and total functional capacity correlated with PET measures of striatal dopamine receptor binding both in the asymptomatic mutation carriers (D1, P < 0.01) and across the combined asymptomatic and clinically affected Huntington's disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET measures of striatal D1 and D2 dopamine binding can be used to identify asymptomatic Huntington's disease mutation carriers who are actively progressing and who would thus be suitable for putative neuroprotective therapies. Measures of disease progression rates in Huntington's disease patients and asymptomatic mutation carriers will be of critical importance in future trials of experimental restorative treatments.274Suhara, T.; Nakayama, K.; Inoue, O.; Fukuda, H.; Shimizu, M.; Mori, A.; Tateno, Y. D1 dopamine receptor binding in mood disorders measured by positron emission tomography. Psychopharmacology. 1992, 106, 14– 18, DOI: 10.1007/BF02253582[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XisFent7w%253D&md5=922b9b183a650b8d099b99d9204907a9D1 dopamine receptor binding in mood disorders measured by positron emission tomographySuhara, Tetsuya; Nakayama, Kazuhiko; Inoue, Osamu; Fukuda, Hiroshi; Shimizu, Makoto; Mori, Atuyoshi; Tateno, YukioPsychopharmacology (Berlin, Germany) (1992), 106 (1), 14-18CODEN: PSCHDL; ISSN:0033-3158.D1 dopamine receptor binding in mood disorders was studied by positron emission tomog. (PET) using 11C-SCH23390. Ten patients with bipolar mood disorders and 21 normal controls were studied in the drug-free state. The patients were in euthymic, depressed, and manic states. Regional radioactivity in the brain was followed for 40 min by PET. A two-compartment model was used to obtain the binding potential (k3/k4) for the striatum and frontal cortex. The binding potentials for the frontal cortex for the patients were lower than those for normal controls, whereas those for striatum were not different. Thus, D1 dopamine receptors in the frontal cortex may be in a different state in patients with bipolar mood disorders.275Dougherty, D. D.; Bonab, A. A.; Ottowitz, W. E.; Livni, E.; Alpert, N. M.; Rauch, S. L.; Fava, M.; Fischman, A. J. Decreased striatal D1 binding as measured using PET and [11C]SCH 23,390 in patients with major depression with anger attacks. Depression Anxiety 2006, 23, 175– 177, DOI: 10.1002/da.20168[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvFamtLg%253D&md5=7312db60a88046a9ee320aa45eb83ab2Decreased striatal D1 binding as measured using PET and [11C]SCH 23,390 in patients with major depression with anger attacksDougherty, Darin D.; Bonab, Ali A.; Ottowitz, William E.; Livni, Eli; Alpert, Nathaniel M.; Rauch, Scott L.; Fava, Maurizio; Fischman, Alan J.Depression and Anxiety (2006), 23 (3), 175-177CODEN: DEANF5; ISSN:1091-4269. (Wiley-Liss, Inc.)This study assessed striatal dopamine 1 (D1) receptor binding in patients with major depressive disorder and anger attacks (MDD + A) and healthy volunteers. We used positron emission tomog. with [11C]SCH 23,390 to compare 10 patients with MDD + A to 10 healthy volunteers. [11C]SCH 23,390 binding in bilateral striata was significantly lower in the MDD + A group when compared to healthy volunteers. These results implicate striatal D1 receptor dysfunction in MDD + A and further suggest an assocn. between dopaminergic transmission and anger or aggression.276Farde, L.; Ehrin, E.; Eriksson, L.; Greitz, T.; Hall, H.; Hedstrom, C. G.; Litton, J. E.; Sedvall, G. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc. Natl. Acad. Sci. U. S. A. 1985, 82, 3863– 3867, DOI: 10.1073/pnas.82.11.3863[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXkvVChsb4%253D&md5=49bcdfa12ec44ea23a8672aab47dcbcdSubstituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomographyFarde, Lars; Ehrin, Erling; Eriksson, Lars; Greitz, Torgny; Hall, Haakan; Hedstroem, Carl Goeran; Litton, Jan Erik; Sedvall, GoeranProceedings of the National Academy of Sciences of the United States of America (1985), 82 (11), 3863-7CODEN: PNASA6; ISSN:0027-8424.[11C]FLB 524 (I) and [11C]raclopride (II) were prepd. and examd. for their possible use as ligands for positron emission tomog. (PET)-scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. II showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of II in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. This and previous in vitro data indicate that II binds selectively to striatal D-2 dopamine receptors. In healthy human subjects, II binding in the caudate nucleus/putamen was 4-5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, II appears to be advantageous with regard to specificity of binding to D-2 receptors, the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and rapid assocn. and reversibility of specific binding. II should be a valuable tool for characterizing D-2 receptors in the brains of patients with neuropsychiatric disorders.277Volkow, N. D.; Fowler, J. S.; Gatley, S. J.; Logan, J.; Wang, G. J.; Ding, Y. S.; Dewey, S. PET Evaluation of the dopamine system of the human brain. J. Nucl. Med. 1996, 37, 1242– 1256[PubMed], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XksF2iu74%253D&md5=9e246c1f3d0dcd420c0075b857d96984PET evaluation of the dopamine system of the human brainVolkow, Nora D.; Fowler, Joanna S.; Gatley, S. John; Logan, Jean; Wang, Gene-Jack; Ding, Yu-Shin; Dewey, StephenJournal of Nuclear Medicine (1996), 37 (7), 1242-1256CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review, with 254 refs. Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are assocd. with many neurol. and psychiatric disorders including Parkinson's disease, schizophrenia and substance abuse. This close assocn. between dopamine and neurol. and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important mol. target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compds. which have specificity for the enzymes which degrade dopamine. Addnl., by using tracers that provide information on regional brain metab. or blood flow as well as neurochem. specific pharmacol. interventions, PET can be used to assess the functional consequences of changes in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurol. diseases. It has also been used in psychopharmacol. research to investigate dopamine drugs used in the treatment of Parkinson's disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurochem. parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. Through the parallel development of new radiotracers, kinetic models and better instruments, PET technol. is enabling investigation of increasingly more complex aspects of the human brain dopamine system. This paper summarizes the different tracers and exptl. strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clin. research.278Politis, M.; Pavese, N.; Tai, Y. F.; Tabrizi, S. J.; Barker, R. A.; Piccini, P. Hypothalamic involvement in Huntington’s disease: An in vivo PET study. Brain 2008, 131, 2860– 2869, DOI: 10.1093/brain/awn244[Crossref], [PubMed], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjhs1yjsw%253D%253D&md5=67786077897c3715f5485cd0786fb2a1Hypothalamic involvement in Huntington's disease: an in vivo PET studyPolitis Marios; Pavese Nicola; Tai Yen F; Tabrizi Sarah J; Barker Roger A; Piccini PaolaBrain : a journal of neurology (2008), 131 (Pt 11), 2860-9 ISSN:.Recent studies have shown alterations in metabolism, sleep and circadian rhythms as well as in several neuropeptides derived from the hypothalamic-pituitary axis in Huntington's disease patients; however, the pathology underlying these abnormalities is not known. Our aim was to assess in vivo D(2) receptor's loss/dysfunction and increases in microglial activation in the hypothalamus of symptomatic Huntington's disease patients and premanifest Huntington's disease gene carriers using PET with (11)C-raclopride (RAC), a specific D(2) receptor ligand and (11)C-(R)-PK11195 (PK), a marker of microglial activation. We have studied 9 symptomatic Huntington's disease patients (age = 46.8 +/- 4.7 years; mean +/- SD) and 10 premanifest Huntington's disease gene carriers (age = 41.9 +/- 8.2 years; mean +/- SD). RAC and PK findings for these subjects were compared with those of a group of normal controls (RAC, n = 9; PK, n = 10). In the symptomatic Huntington's disease group, we found a significant decrease (P = 0.0012) in mean hypothalamic RAC binding potential (BP) and a significant increase in mean hypothalamic PK BP (P = 0.0008). Similarly, a significant decrease (P = 0.0143) in mean hypothalamic RAC BP and a significant increase in mean hypothalamic PK BP (P = 0.0057) were observed in the premanifest Huntington's disease group. Hypothalamic RAC and PK BP values correlated with each other in combined Huntington's disease groups (r = -0.6180, P = 0.0048) but not with striatal RAC and PK BP values. Our data demonstrate, for the first time, significant D(2) receptor loss and microglia activation in the hypothalamus of Huntington's disease. These pathological changes occur very early in the course of the disease and may partly explain the development of commonly reported symptoms in Huntington's disease including progressive weight loss, alterations in sexual behaviour and disturbances in the wake-sleep cycle.279Antonini, A.; Leenders, K. L.; Spiegel, R.; Meier, D.; Vontobel, P.; Weigell-Weber, M.; Sanchez-Pernaute, R.; de Yébenez, J. G.; Boesiger, P.; Weindl, A.; Maguire, R. P. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain 1996, 119, 2085– 2095, DOI: 10.1093/brain/119.6.2085[Crossref], [PubMed], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7mtlWktQ%253D%253D&md5=1a4959fc0a6d7f289ad1db0b26092ad1Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington's diseaseAntonini A; Leenders K L; Spiegel R; Meier D; Vontobel P; Weigell-Weber M; Sanchez-Pernaute R; de Yebenez J G; Boesiger P; Weindl A; Maguire R PBrain : a journal of neurology (1996), 119 ( Pt 6) (), 2085-95 ISSN:0006-8950.We used PET scans with the tracers [18F]fluorodeoxyglucose (FDG) and [11C]raclopride (RACLO) to study glucose metabolism and dopamine D2 receptor binding in the caudate nucleus and putamen of 18 carriers of the Huntington's disease gene mutation (10 asymptomatic subjects and eight untreated symptomatic Huntington's disease patients in an early disease stage). We also performed MRI scans and measured the bicaudate ratio (BCR) in the same subjects. Data were compared with those from nine mutation-negative members of Huntington's disease families and separate groups of age matched controls. The PET scans were repeated 1.5-3 years later in six of the asymptomatic gene carriers. Symptomatic Huntington's disease patients showed a marked reduction of FDG and RACLO uptake in the caudate nucleus and putamen and a significant increase of BCR. Asymptomatic mutation carriers revealed significant hypometabolism in the caudate nucleus and putamen. The RACLO binding was significantly decreased in the putamen. Decrements of caudate nucleus tracer uptake, particularly RACLO, correlated significantly with BCR increases in both symptomatic and asymptomatic gene carriers. In asymptomatic carriers, metabolic and receptor binding decreases were also significantly associated with the CAG repeat number but not with the individual's age. Discriminant function analysis correctly classified clinical and genetic status in 24 of 27 subjects on the basis of their striatal PET values (83% sensitivity and 100% specificity). Three asymptomatic mutation carriers were classified/grouped together with mutation-negative subjects, indicating that these individuals had normal striatal RACLO and FDG uptake. Follow-up PET data from gene-positive subjects showed a significant reduction in the mean striatal RACLO binding of 6.3% per year. Striatal glucose metabolism revealed an overall non significant 2.3% decrease per year. These data indicate that asymptomatic Huntington's disease mutation carriers may show normal neuronal function for a long period of life. These findings also suggest that it may be possible to predict when an asymptomatic gene carrier will develop clinical symptoms from serial PET measurements of striatal function.280Pavese, N.; Andrews, T. C.; Brooks, D. J.; Ho, A. K.; Rosser, A. E.; Barker, R. A.; Robbins, T. W.; Sahakian, B. J.; Dunnett, S. B.; Piccini, P. Progressive striatal and cortical dopamine receptor dysfunction in Huntington’s disease: A PET study. Brain 2003, 126, 1127– 1135, DOI: 10.1093/brain/awg119[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s7ntVylsg%253D%253D&md5=17daaaea7f6b647540f27331f9118e09Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET studyPavese Nicola; Andrews Thomasin C; Brooks David J; Ho Aileen K; Rosser Anne E; Barker Roger A; Robbins Trevor W; Sahakian Barbara J; Dunnett Stephen B; Piccini PaolaBrain : a journal of neurology (2003), 126 (Pt 5), 1127-35 ISSN:0006-8950.We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.281Tang, C. C.; Feigin, A.; Ma, Y.; Habeck, C.; Paulsen, J. S.; Leenders, K. L.; Teune, L. K.; van Oostrom, J. C. H.; Guttman, M.; Dhawan, V.; Eidelberg, D. Metabolic network as a progression biomarker of premanifest Huntington’s disease. J. Clin. Invest. 2013, 123, 4076– 4088, DOI: 10.1172/JCI69411[Crossref], [PubMed], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVemsrzK&md5=5e6229eb7e38ba606f0317985acd415cMetabolic network as a progression biomarker of premanifest Huntington's diseaseTang, Chris C.; Feigin, Andrew; Ma, Yilong; Habeck, Christian; Paulsen, Jane S.; Leenders, Klaus L.; Teune, Laura K.; van Oostrom, Joost C. H.; Guttman, Mark; Dhawan, Vijay; Eidelberg, DavidJournal of Clinical Investigation (2013), 123 (9), 4076-4088CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)Background: The evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network assocd. with the progression of preclin. Huntington's disease (HD). Methods: Twelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue vol. The rate of metabolic network progression in this cohort was compared with the corresponding est. obtained in a sep. group of 21 premanifest HD carriers who were scanned twice over a 2-yr period. Results: In the original premanifest cohort, network anal. disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approx. twice the rate of single region measurements from the same subjects. Conclusion: Metabolic network measurements provide a sensitive means of quant. evaluating disease progression in premanifest individuals. This approach may be incorporated into clin. trials to assess disease-modifying agents.282van Oostrom, J. C. H.; Maguire, R. P.; Verschuuren-Bemelmans, C. C.; Veenma-Van der Duin, L.; Pruim, J.; Roos, R. A. C.; Leenders, K. L. Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease. Neurology 2005, 65, 941– 943, DOI: 10.1212/01.wnl.0000176071.08694.cc[Crossref], [PubMed], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpslyksrc%253D&md5=32f3275fdac80512d466a0a149fb4ea1Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington diseasevan Oostrom, J. C. H.; Maguire, R. P.; Verschuuren-Bemelmans, C. C.; Veenma-van der Duin, L.; Pruim, J.; Roos, R. A. C.; Leenders, K. L.Neurology (2005), 65 (6), 941-943CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Among 27 preclin. carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the product of age and CAG repeat length (p < 0.0005). Dopamine D2 receptor availability measured by RAC-BP seems the most sensitive indicator of early neuronal impairment in PMC.283Antonini, A.; Leenders, K. L.; Eidelberg, D. [11C]raclopride-PET studies of the Huntington’s disease rate of progression: relevance of the trinucleotide repeat length. Ann. Neurol. 1998, 43, 253– 255, DOI: 10.1002/ana.410430216[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1c7ktlKjsw%253D%253D&md5=2c04602444e09df172245550a93585ef11C]raclopride-PET studies of the Huntington's disease rate of progression: relevance of the trinucleotide repeat lengthAntonini A; Leenders K L; Eidelberg DAnnals of neurology (1998), 43 (2), 253-5 ISSN:0364-5134.We used [11C]raclopride and positron emission tomography (PET) to assess the relationship between striatal dopamine D2 receptor binding, trinucleotide repeat number (CAG), and subject age in 10 asymptomatic and 8 symptomatic carriers of the Huntington's disease (HD) mutation. In both preclinical and symptomatic gene carriers, we found significant correlations between CAG repeat length and the ratio of percent loss in striatal D2 receptor binding divided by age. In accord with neuropathological studies, we obtained an intercept at 35.5 CAG repeats in the symptomatic HD patients. Nonetheless, we noted that the slopes of the correlation lines differed significantly for the presymptomatic and symptomatic cohorts. These PET results support the notion that the HD disease process is a function of trinucleotide length and age, and that the development of clinical signs and symptoms is associated with CAG repeat lengths greater than 35.5. However, our analysis also suggests that striatal degeneration may proceed in a nonlinear fashion. These findings have implications for the design of neuroprotective strategies for the treatment of HD.284Pavese, N.; Politis, M.; Tai, Y. F.; Barker, R. A.; Tabrizi, S. J.; Mason, S. L.; Brooks, D. J.; Piccini, P. Cortical dopamine dysfunction in symptomatic and premanifest Huntington’s disease gene carriers. Neurobiol. Dis. 2010, 37, 356– 361, DOI: 10.1016/j.nbd.2009.10.015[Crossref], [PubMed], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXos1Cl&md5=2fa3582d26f14134e23fc1085dbfaf4eCortical dopamine dysfunction in symptomatic and premanifest Huntington's disease gene carriersPavese, Nicola; Politis, Marios; Tai, Yen F.; Barker, Roger A.; Tabrizi, Sarah J.; Mason, Sarah L.; Brooks, David J.; Piccini, PaolaNeurobiology of Disease (2010), 37 (2), 356-361CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)We used 11C-raclopride PET, a marker of D2 dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D2 receptor dysfunction in individual Huntington's disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clin. significance. 62.5% Of symptomatic HD patients and 54.5% of premanifest carriers showed cortical redns. in D2 binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D2 binding had worse scores on neuropsychol. tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable redn. in striatal D2 binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiol. and could contribute to the impairment in neuropsychol. performance in these patients.285Esmaeilzadeh, M.; Farde, L.; Karlsson, P.; Varrone, A.; Halldin, C.; Waters, S.; Tedroff, J. Extrastriatal dopamine D2 receptor binding in Huntington’s disease. Hum. Brain Mapp. 2011, 32, 1626– 1636, DOI: 10.1002/hbm.21134[Crossref], [PubMed], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MfitVKqsQ%253D%253D&md5=defaf31f9ecfacee241cfc3ab7ed3d19Extrastriatal dopamine D(2) receptor binding in Huntington's diseaseEsmaeilzadeh Mouna; Farde Lars; Karlsson Per; Varrone Andrea; Halldin Christer; Waters Susanna; Tedroff JoakimHuman brain mapping (2011), 32 (10), 1626-36 ISSN:.Huntington's disease (HD) is a neurodegenerative disorder, primarily affecting medium spiny neurones in the striatum. The density of striatal dopamine D(2) receptors is reduced in HD but there is little known about this biomarker in brain regions outside the striatum. The primary objective of this study was to compare extrastriatal dopamine D(2) receptor binding, in age-matched control subjects and patients with HD. All subjects were examined using a high-resolution positron emission tomography system and the high-affinity dopamine D(2) receptor radioligand [(11) C]FLB 457. A ROI based analysis was used with an atrophy correction method. Dopamine D(2) receptor binding potential was reduced in the striatum of patients with HD. Unlike the striatum, dopamine D(2) receptor binding in thalamic and cortical subregions was not significantly different from that in control subjects. A partial least square regression analysis which included binding potential values from all investigated cortical and subcortical regions revealed a significant model separating patients from controls, conclusively dependent on differences in striatal binding of the radioligand. Some clinical assessments correlated with striatal dopamine D(2) receptor binding, including severity of chorea and cognitive test performance. Hence, the present study demonstrates that dopamine D(2) receptors extrinsic to the striatum are well preserved in early to mid stage patients with HD. This observation may have implication for the development of therapy for HD.286Volkow, N. D.; Wang, G.-J.; Fowler, J. S.; Thanos, P.; Logan, J.; Gatley, S. J.; Gifford, A.; Ding, Y.-S.; Wong, C.; Pappas, N. Brain DA D2 receptors predict reinforcing effects of stimulants in humans: Replication study. Synapse 2002, 46, 79– 82, DOI: 10.1002/syn.10137[Crossref], [PubMed], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XnvFKit7o%253D&md5=e8874419f52619355da2d9991915141dBrain DA D2 receptors predict reinforcing effects of stimulants in humans: replication studyVolkow, Nora D.; Wang, Gene-Jack; Fowler, Joanna S.; Thanos, Pether; Logan, Jean; Gatley, Samuel J.; Gifford, Andrew; Ding, Yu-Shin; Wong, Chris; Pappas, NaomiSynapse (New York, NY, United States) (2002), 46 (2), 79-82CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)We had shown that striatal DA D2 receptors levels predicted the reinforcing responses to the psychostimulant drug methylphenidate in nondrug-abusing subjects. Here, we assessed the replicability of this finding. We measured D2 receptors with PET and [11C]raclopride (twice to det. stability) in seven nondrug-abusing subjects to assess if they predicted the self-reports of "drug-liking" to i.v. methylphenidate (0.5 mg/kg). DA D2 measures were significantly correlated with "drug-liking" in both evaluations (r = 0.82 and r = 0.78); subjects with the lowest levels reported the higher ratings of "drug-liking" and vice versa. These results replicate our previous findings and provide further evidence that striatal DA D2 receptors modulate reinforcing responses to stimulants in humans and may underlie predisposition for drug self-administration.287Volkow, N. D.; Wang, G.-J.; Begleiter, H.; Porjesz, B.; Fowler, J. S.; Telang, F.; Wong, C.; Ma, Y.; Logan, J.; Goldstein, R.; Alexoff, D.; Thanos, P. K. High levels of dopamine D2 receptors in unaffected members of alcoholic families: Possible protective factors. Arch. Gen. Psychiatry 2006, 63, 999– 1008, DOI: 10.1001/archpsyc.63.9.999[Crossref], [PubMed], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVamtr7I&md5=c25bb3df43eb333ceca2bc75293529ffHigh levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factorsVolkow, Nora D.; Wang, Gene-Jack; Begleiter, Henri; Porjesz, Bernice; Fowler, Joanna S.; Telang, Frank; Wong, Christopher; Ma, Yeming; Logan, Jean; Goldstein, Rita; Alexoff, David; Thanos, Peter K.Archives of General Psychiatry (2006), 63 (9), 999-1008CODEN: ARGPAQ; ISSN:0003-990X. (American Medical Association)Context: Predisposition to alcoholism is likely an interaction between genetic and environmental factors that confer vulnerability and protection. Alc. subjects have low levels of dopamine D2 receptors in striatum, and increasing D2 receptor levels in lab. animals reduces alc. consumption. Objectives: To test whether high levels of D2 receptors may be protective against alcoholism and whether this is mediated by their modulation of activity in orbitofrontal cortex and cingulate gyrus (regions involved in salience attribution, emotional reactivity, and inhibitory control). Design: Research (nonalcoholic subjects with a family history of alcoholism) and comparison (nonalcoholic subjects with a neg. family history) sample. Setting: Outpatient setting. Participants: Fifteen nonalcoholic subjects who had an alc. father and at least 2 other first- or second-degree relatives who were alcoholics (family-pos. group) and 16 nonalcoholic controls with no family history of alcoholism (family-neg. group). Main Outcome Measures: Results of positron emission tomog. with raclopride C 11 to assess D2 receptors and with fludeoxyglucose F 18 to assess brain glucose metab. (marker of brain function). Personality measures were obtained with the Multidimensional Personality Questionnaire. Results: Availability of D2 receptors was significantly higher in caudate and ventral striatum in family-pos. than family-neg. subjects. In family-pos. but not family-neg. subjects, striatal D2 receptors were assocd. with metab. in anterior cingulate (Brodmann area 24/25) and orbitofrontal (Brodmann area 11) and prefrontal (Brodmann area 9/10) cortices, and with personality scores of pos. emotionality. Conclusions: The higher-than-normal D2 receptor availability in nonalcoholic members of alc. families supports the hypothesis that high levels of D2 receptors may protect against alcoholism. The significant assocns. between D2 receptors and metab. in frontal regions involved with emotional reactivity and executive control suggest that high levels of D2 receptors could protect against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions.288Olsson, H.; Halldin, C.; Farde, L. Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. NeuroImage 2004, 22, 794– 803, DOI: 10.1016/j.neuroimage.2004.02.002[Crossref], [PubMed], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c3ptlKqtw%253D%253D&md5=040da3cddfdfa39f476eff4d7aa8b2c3Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PETOlsson Hans; Halldin Christer; Farde LarsNeuroImage (2004), 22 (2), 794-803 ISSN:1053-8119.Dopaminergic neurotransmission in extrastriatal regions may play a crucial role in the pathophysiology and treatment of neuropsychiatric disorders. The high-affinity radioligands [(11)C]FLB 457, [(123)I]epidepride, and [(18)F]fallypride are now used in clinical studies to measure these low-density receptor populations in vivo. However, a single determination of the regional binding potential (BP) does not differentiate receptor density (B(max)) from the apparent affinity (K(D)). In this positron emission tomography (PET) study, we measured extrastriatal dopamine D2 receptor density (B(max)) and apparent affinity (K(D)) in 10 healthy subjects using an in vivo saturation approach. Each subject participated in two to three PET measurements with different specific radioactivity of [(11)C]FLB 457. The commonly used simplified reference tissue model (SRTM) was used in a comparison of BP values with the B(max) values obtained from the saturation analysis. The calculated regional receptor density values were of the same magnitude (0.33-1.68 nM) and showed the same rank order as reported from postmortem studies, that is, in descending order thalamus, lateral temporal cortex, anterior cinguli, and frontal cortex. The affinity ranged from 0.27 to 0.43 nM, that is, approximately 10-20 times the value found in vitro (20 pM). The area under the cerebellar time activity curve (TAC) was slightly lower (11 +/- 8%, mean +/- SD, P = 0.004, n = 10) after injection of low as compared with high specific radioactivity, indicating sensitivity to the minute density of dopamine D2 receptors in the this region. The results of the present study support that dopamine D2 receptor density and affinity can be differentiated in low-density regions using a saturation approach. There was a significant (P < 0.001) correlation between the binding potential calculated with SRTM and the receptor density (B(max)), which supports the use of BP in clinical studies where differentiation of B(max) and K(D) is not required. In such studies, the mass of FLB 457 has to be less than 0.5 microg injected to avoid a mass effect of the radioligand itself.289Sudo, Y.; Suhara, T.; Inoue, M.; Ito, H.; Suzuki, K.; Saijo, T.; Halldin, C.; Farde, L. Reproducibility of [11C]FLB 457 binding in extrastriatal regions. Nucl. Med. Commun. 2001, 22, 1215– 1221, DOI: 10.1097/00006231-200111000-00008[Crossref], [PubMed], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXoslSrtLs%253D&md5=3a17b24e65c8e0b06f59fb57d14b5b6eReproducibility of [11C]FLB 457 binding in extrastriatal regionsSudo, Y.; Suhara, T.; Inoue, M.; Ito, H.; Suzuki, K.; Saijo, T.; Halldin, C.; Farde, L.Nuclear Medicine Communications (2001), 22 (11), 1215-1221CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)Extrastriatal D2 dopamine receptors represent an important target of research into the pathophysiol. and pharmacotherapy of psychiatric disorders. The high affinity radioligand [11C]FLB 457 makes possible the measurement of low concns. of D2 receptors in extrastriatal regions using positron emission tomog. (PET). The aim of this study was to assess the test/retest variability and reliability of [11C]FLB 457 binding using a ref. tissue model. Eight healthy male subjects (aged 20-33 yr) underwent two [11C]FLB 457 PET examns. Radioactivity in the cerebellum was used as the ref. The binding potentials (BPs) for five cortical regions of interest (ROIs) were calcd. using the ref. tissue model. The BP was also calcd. for each pixel in the form of parametric images. Reproducibility was assessed both for the ROI method and for the parametric images. The test/retest reproducibility for [11C]FLB 457 binding was good, with a mean variability ranging from 4.5% for the thalamus to 15.5% for the hippocampus. The parametric images also demonstrated good reproducibility. These results support the suitability of using [11C]FLB 457 for the quant. evaluation of extrastriatal D2 receptors and for protocols requiring repeated measurements in the same individual.290Suhara, T.; Sudo, Y.; Okauchi, T.; Maeda, J.; Kawabe, K.; Suzuki, K.; Okubo, Y.; Nakashima, Y.; Ito, H.; Tanada, S.; Halldin, C.; Farde, L. Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET. Int. J. Neuropsychopharmacol. 1999, 2, 73– 82, DOI: 10.1017/S1461145799001431[Crossref], [PubMed], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXlvVans7c%253D&md5=cf8b85307fdcb46720785001d21b1e03Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PETSuhara, Tetsuya; Sudo, Yasuhiko; Okauchi, Takashi; Maeda, Jun; Kawabe, Koichi; Suzuki, Kazutoshi; Okubo, Yoshiro; Nakashima, Yoshifumi; Ito, Hiroshi; Tanada, Shuji; Halldin, Christer; Farde, LarsInternational Journal of Neuropsychopharmacology (1999), 2 (2), 73-82CODEN: IJNUFB; ISSN:1461-1457. (Cambridge University Press)The aim of the present study was to quantify the d. and affinity of human extrastriatal dopamine D2 receptors using positron emission tomog. (PET). [11C]FLB-457, a high-affinity dopamine D2 receptor antagonist with various specific radioactivities (SA) was used. Eight healthy male subjects, age 20-35 yr, participated twice or three times at different SAs (1-279 GBq/μmol), and serial dynamic scans were performed in the 3D data acquisition mode. The peak of the specific binding was not well defined with high SA due to the flatness of the curves after 60 min but was obsd. within the PET measurement. In the expt. with low SA, the peak came earlier than that with high SA. Scatchard anal. was performed using the maximal specific binding value (transient equil.) and the radioactivity in the cerebellum as free ligand concn. The highest d. was obsd. in the thalamus (2.3 ± 0.6 pmol/mL), followed by the temporal cortex (1.5 ± 0.5 pmol/mL), hippocampus (1.4 ± 0.5 pmol/mL), parietal cortex (0.9 ± 0.4 pmol/mL), frontal cortex (0.8 ± 0.2 pmol/mL) and occipital cortex (0.7 ± 0.3 pmol/mL). There was no significant difference in Kd values in these six regions. The present results demonstrate that dopamine D2 receptor densities in the extrastriatal regions were only 2-8% of that in the striatum. Although the d. of extrastriatal dopamine D2 receptor was low, significant regional differences were obsd. in the present study, as reported in postmortem studies.291Vilkman, H.; Kajander, J.; Någren, K.; Oikonen, V.; Syvälahti, E.; Hietala, J. Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457 - A test-retest analysis. Eur. J. Nucl. Med. Mol. Imaging 2000, 27, 1666– 1673, DOI: 10.1007/s002590000342292Montgomery, A. J.; Stokes, P.; Kitamura, Y.; Grasby, P. M. Extrastriatal D2 and striatal D2 receptors in depressive illness: Pilot PET studies using [11C]FLB 457 and [11C]raclopride. J. Affective Disord. 2007, 101, 113– 122, DOI: 10.1016/j.jad.2006.11.010[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtlSntrc%253D&md5=db5998e35ab4b48889fe732cdfdb6527Extrastriatal D2 and striatal D2 receptors in depressive illness: Pilot PET studies using [11C]FLB 457 and [11C]racloprideMontgomery, Andrew J.; Stokes, Paul; Kitamura, Yuri; Grasby, Paul M.Journal of Affective Disorders (2007), 101 (1-3), 113-122CODEN: JADID7; ISSN:0165-0327. (Elsevier Ltd.)Reduced dopaminergic function may occur in depressive disorders. In this paper the results of two pilot studies examg. different aspects of the dopamine system in depression are presented. First, the binding of [11C]FLB 457 to extrastriatal D2 receptors was measured in a group of depressed patients. Second, the hypothesis that selective serotonin reuptake inhibiting (SSRI) antidepressants affect the striatal binding of [11C]raclopride was tested. In the first study the binding of [11C]FLB 457 was compared between 7 people with depression and 7 healthy controls. In the second study the binding of [11C]raclopride to striatal D2/3 receptors was compared between 8 people taking SSRI antidepressant medication and 8 healthy controls. There was no difference in the binding of [11C]FLB 457 between the two groups. [11C]raclopride binding was reduced in the dorsal striatum of people taking antidepressants suggesting either that D2/3 expression was reduced, or that dopamine release was increased, compared to untreated controls. The depressed patients were not severely depressed and were not matched for gender with controls. In the raclopride group the patients and controls were not matched by gender and were taking different SSRI antidepressants. We found no support for the hypothesis that dopamine D2 receptor expression is altered in extrastriatal brain regions in depression. SSRI antidepressants were assocd. with reduced [11C]raclopride binding in the dorsal striatum supporting the hypothesis that therapeutic effects of such drugs may, in part, be due to changes in the dopamine system.293Saijo, T.; Takano, A.; Suhara, T.; Arakawa, R.; Okumura, M.; Ichimiya, T.; Ito, H.; Okubo, Y. Electroconvulsive therapy decreases dopamine D2 receptor binding in the anterior cingulate in patients with depression: A controlled study using positron emission tomography with radioligand [11C]FLB 457. J. Clin. Psychiatry 2010, 71, 793– 799, DOI: 10.4088/JCP.08m04746blu[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3crovVGltw%253D%253D&md5=a9693e60a6bf0e7c9b2c9a32b2616d29Electroconvulsive therapy decreases dopamine D2receptor binding in the anterior cingulate in patients with depression: a controlled study using positron emission tomography with radioligand [11C]FLB 457Saijo Tomoyuki; Takano Akihiro; Suhara Tetsuya; Arakawa Ryosuke; Okumura Masaki; Ichimiya Tetsuya; Ito Hiroshi; Okubo YoshiroThe Journal of clinical psychiatry (2010), 71 (6), 793-9 ISSN:.OBJECTIVE: Electroconvulsive therapy (ECT) has been confirmed as one of the most effective treatments in drug-resistant major depression. However, the mechanism of ECT is still poorly understood. Although several lines of studies have focused on its effect on dopamine neurotransmission, the effects of ECT on dopamine D(2) receptors in a living human brain have not been investigated. Using positron emission tomography (PET) scans with the radioligand [(11)C]FLB 457, we aimed to evaluate the effect of ECT on extrastriatal D(2) receptor binding in medicated patients with major depressive disorder (MDD). METHOD: Seven patients with a DSM-IV diagnosis of MDD underwent PET scans before and after a series of 6-7 treatments with bilateral ECT. Eleven healthy controls were scanned for comparison. All participants were scanned at the National Institute of Radiological Sciences, Chiba, Japan, between November 2000 and September 2005. The parametric images of [(11)C]FLB 457 binding were generated on the basis of a simplified reference tissue model. Voxel-based methods were used to assess the effect of ECT on D(2) receptor binding. RESULTS: There were no significant differences in D(2) receptor binding between patients with MDD and controls. All 7 patients showed clinical improvements in response to ECT treatment (P < .001). Significant changes in D(2) receptor binding, a mean of 25.2% reduction, were found in the right rostral anterior cingulate (AC) following ECT (P < .001). CONCLUSIONS: Electroconvulsive therapy decreased D(2) receptor binding in the rostral AC in MDD patients responding to ECT. Our finding suggests that one of the biologic mechanisms of ECT could be related to dopaminergic alteration in the rostral AC.294Turjanski, N.; Weeks, R.; Dolan, R.; Harding, A. E.; Brooks, D. J. Striatal D1 and D2 receptor binding in patients with Huntington’s disease and other choreas A PET study. Brain 1995, 118, 689– 696, DOI: 10.1093/brain/118.3.689[Crossref], [PubMed], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2MzitlCnug%253D%253D&md5=f3d6c0346ed8a7a88757aecdfeb78402Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET studyTurjanski N; Weeks R; Dolan R; Harding A E; Brooks D JBrain : a journal of neurology (1995), 118 ( Pt 3) (), 689-96 ISSN:0006-8950.We have used PET to study striatal D1 and D2 receptor binding in 10 patients with either the choreic or akinetic-rigid variants of Huntington's disease and in three patients with other causes of chorea. Background rigidity and bradykinesia in choreic patients were scored with a four-point scale. PET studies showed a severe and parallel reduction of both striatal D1 and D2 receptor binding in Huntington's disease patients irrespective of their predominant phenotype (mean reduction 60%). Huntington's disease patients with rigidity showed more pronounced reduction of striatal D1 and D2 binding compared with those without rigidity. A case of chorea associated with systemic lupus erythematosus had normal D2 binding. These results suggest that the presence of chorea per se may not be determined by alterations in striatal dopamine receptor binding, but that rigidity in Huntington's disease is associated with severe striatal D1 and D2 receptor loss.295Pearlson, G. D. In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder. Arch. Gen. Psychiatry 1995, 52, 471– 477, DOI: 10.1001/archpsyc.1995.03950180057008[Crossref], [PubMed], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2M3ovFylsQ%253D%253D&md5=5316e84108e2af3ad2c9c20fcd1c9e2fIn vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorderPearlson G D; Wong D F; Tune L E; Ross C A; Chase G A; Links J M; Dannals R F; Wilson A A; Ravert H T; Wagner H N JrArchives of general psychiatry (1995), 52 (6), 471-7 ISSN:0003-990X.BACKGROUND: A prior positron emission tomographic study from The Johns Hopkins University, Baltimore, Md, using N-methylspiperone labeled with carbon 11 reported elevated basal ganglia D2 dopamine receptor density (Bmax) values in neuroleptic-naive schizophrenic patients compared with controls. We have now extended these studies to include patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 14) either had never received neuroleptic medication or had been neuroleptic-free for more than 6 months, and they met DSM-III criteria for currently symptomatic affective disorder. Patients with bipolar disorder were compared with matched schizophrenic patients and normal controls. All received two positron emission tomographic scans, the second of which was preceded by oral administration of haloperidol lactate, to permit the calculation of D2 dopamine receptor Bmax. RESULTS: Diagnostic groups differed in Bmax by analysis of variance (P < .0001); post hoc tests showed higher Bmax values for psychotic patients with bipolar disorder and schizophrenic patients compared with normal controls and for schizophrenic patients and psychotic patients with bipolar disorder compared with nonpsychotic patients with bipolar disorder. Among patients with bipolar disorder, Bmax values correlated significantly with the severity of psychotic symptoms (r = .63) on the Present State Examination but not with the severity of nonpsychotic mood symptoms. CONCLUSIONS: We conclude that, like schizophrenic patients, patients with psychotic bipolar disorder have elevations of D2 dopamine receptor Bmax values and that such elevations in affective disorder are more closely associated with the presence of psychosis than with mood abnormality. Elevations in dopamine receptor values thus may occur in psychiatric states that are characterized by psychotic symptoms rather than being specific to schizophrenia.296Wong, D. F.; Pearlson, G. D.; Tune, L. E.; Young, L. T.; Meltzer, C. C.; Dannals, R. F.; Ravert, H. T.; Reith, J.; Kuhar, M. J.; Gjedde, A. Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness. J. Cereb. Blood Flow Metab. 1997, 17, 331– 342, DOI: 10.1097/00004647-199703000-00010[Crossref], [PubMed], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3ktlCmsg%253D%253D&md5=c51468ca6ffe327c1d58cd27fc62741eQuantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illnessWong D F; Pearlson G D; Tune L E; Young L T; Meltzer C C; Dannals R F; Ravert H T; Reith J; Kuhar M J; Gjedde AJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (1997), 17 (3), 331-42 ISSN:0271-678X.In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C]methyl-spiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.297Brooks, D. J. Imaging approaches to Parkinson disease. J. Nucl. Med. 2010, 51, 596– 609, DOI: 10.2967/jnumed.108.059998[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXls12guro%253D&md5=9e3aadb751395e2d59574b11d52e924eImaging approaches to Parkinson diseaseBrooks, David J.Journal of Nuclear Medicine (2010), 51 (4), 596-609CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review. Parkinson disease (PD) is assocd. with nigral degeneration and striatal dopamine deficiency. Demonstrating midbrain structural abnormalities with transcranial sonog. or diffusion-weighted MRI or showing striatal dopamine terminal dysfunction with PET or SPECT supports the diagnosis and rationalizes the use of dopaminergic medications. In atypical PD variants, transcranial sonog. can detect striatal hyperechogenicity, and diffusion-weighted imaging can detect increased putamen water diffusion, whereas 18F-FDG PET reveals reduced lentiform nucleus glucose metab. PET and SPECT can detect changes in striatal dopamine levels after levodopa administration and relate these to motor responses. Loss of cortical dopaminergic and cholinergic function is present in demented PD and, on occasion, amyloid deposits can be detected. Loss of cardiac sympathetic innervation can be sensitively detected in PD with 18F-dopamine PET or 123I-metaiodobenzylguanidine SPECT. Finally, PET can detect widespread brain inflammation in PD. This review discusses the role of structural and functional imaging for diagnosing and managing different parkinsonian syndromes.298Brooks, D. J.; Ibanez, V.; Sawle, G. V.; Playford, E. D.; Quinn, N.; Mathias, C. J.; Lees, A. J.; Marsden, C. D.; Bannister, R.; Frackowiak, R. S. J. Striatal D2 receptor status in patients with Parkinson’s disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann. Neurol. 1992, 31, 184– 192, DOI: 10.1002/ana.410310209[Crossref], [PubMed], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK383ks1ClsQ%253D%253D&md5=3eba2f143bab790eef32cf542d4dac06Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomographyBrooks D J; Ibanez V; Sawle G V; Playford E D; Quinn N; Mathias C J; Lees A J; Marsden C D; Bannister R; Frackowiak R SAnnals of neurology (1992), 31 (2), 184-92 ISSN:0364-5134.Equilibrium striatal: cerebellar 11C-raclopride (RAC) uptake ratios reflect the density of striatal dopamine D2 binding sites. Using positron emission tomographic scanning we have measured striatal RAC uptake in 6 untreated patients with Parkinson's disease (PD), 5 chronically treated patients with PD and a fluctuating response to L-dopa, 10 patients with striatonigral degeneration (SND), and 9 patients with progressive supranuclear palsy (PSP). Regional cerebral blood flow was determined also, with C15O2. Mean striatal: cerebellar RAC uptake was not significantly different from normal in untreated patients with PD, though 2 of these 6 patients showed significantly increased putamen tracer binding. Mean caudate and putamen: cerebellar RAC uptake ratios of the group with PD and a fluctuating response to L-dopa were significantly reduced by 30% and 18%, respectively. The patients with SND had lesser, but significant, 10% and 11% decreases in mean caudate and putamen: cerebellar RAC uptake ratios, respectively, whereas patients with PSP showed 24% and 9% reductions in caudate and putamen: cerebellar RAC binding. Striatal and frontal blood flow were significantly reduced in patients with PSP, but not in patients with PD or SND. In conclusion, striatal D2 binding potential is normal or raised in untreated patients with PD, but reduced in patients with PD and a fluctuating response to L-dopa. Patients with SND and PSP show a decrease in striatal RAC binding, but to a lesser extent than patients with PD and a fluctuating response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)299Antonini, A.; Schwarz, J.; Oertel, W. H.; Beer, H. F.; Madeja, U. D.; Leenders, K. L. [11C]Raclopride and positron emission tomography in previously untreated patients with Parkinson’s disease: Influence of L-dopa and lisuride therapy on striatal dopamine D2-receptors. Neurology 1994, 44, 1325– 1325, DOI: 10.1212/WNL.44.7.1325[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2czgvFyhsg%253D%253D&md5=89a69320fa0bfe8776211a5e6431d42a11C]raclopride and positron emission tomography in previously untreated patients with Parkinson's disease: Influence of L-dopa and lisuride therapy on striatal dopamine D2-receptorsAntonini A; Schwarz J; Oertel W H; Beer H F; Madeja U D; Leenders K LNeurology (1994), 44 (7), 1325-9 ISSN:0028-3878.We studied cerebral dopamine D2-receptor binding using [11C]raclopride and PET in 18 previously untreated patients with Parkinson's disease (PD) and 14 healthy volunteer subjects. Sixteen patients were scanned before and after 3 to 4 months of stable oral therapy with either L-dopa (300 mg/d) (n = 7) or lisuride (0.8 to 1.2 mg/d) (n = 9). Two additional patients were investigated before and after a continuous IV infusion of L-dopa. In addition, we studied the effect of acute IV L-dopa and lisuride administration on [11C]raclopride binding in a healthy rhesus monkey. At baseline, PD patients showed higher uptake values in the putamen than did healthy subjects (p < 0.0001). Oral lisuride treatment lowered [11C]raclopride uptake in the putamen (-19%) and in the caudate nucleus (-15%) compared with baseline, but the difference did not reach significance upon Bonferroni correction for multiple comparisons. However, putamen tracer uptake returned to baseline in two patients when we repeated [11C]raclopride scans 4 days after lisuride withdrawal. Oral L-dopa treatment did not induce changes in the putamen or caudate nucleus indices. Acute lisuride (25 micrograms) administration in a healthy monkey reduced striatal uptake values, but acute injection of L-dopa (300 mg) did not. The results suggest that lisuride blocks [11C]raclopride binding at dopamine D2-receptor sites and demonstrate that 3 to 4 months' oral therapy with L-dopa or lisuride does not change striatal dopamine D2-receptor density in PD patients.300Antonini, A.; Schwarz, J.; Oertel, W. H.; Pogarell, O.; Leenders, K. L. Long-term changes of striatal dopamine D2 Receptors in patients with Parkinson’s disease: A study with positron emission tomography and [11C]raclopride. Mov. Disord. 1997, 12, 33– 38, DOI: 10.1002/mds.870120107[Crossref], [PubMed], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7ksVahtw%253D%253D&md5=b412f5b912793aec2645ad8c6aa92756Long-term changes of striatal dopamine D2 receptors in patients with Parkinson's disease: a study with positron emission tomography and [11C]racloprideAntonini A; Schwarz J; Oertel W H; Pogarell O; Leenders K LMovement disorders : official journal of the Movement Disorder Society (1997), 12 (1), 33-8 ISSN:0885-3185.We used [11C]raclopride (RACLO) and positron emission tomography (PET) to study longitudinally striatal dopamine D2 receptor binding in nine patients with Parkinson's disease (PD) at an early drug-naive stage and 3-5 years later, when motor fluctuations had appeared in seven of them. Patients were treated with a combination of levodopa and dopamine agonists. Data were compared with 10 healthy controls in the same age range. Initially, patients with PD showed a significant increase of RACLO uptake in the putamen compared with controls (p < 0.04). The caudate nucleus revealed values in the normal range. After 3-5 years, RACLO binding was significantly reduced in the putamen (p < 0.03) and caudate nucleus (p < 0.03) compared with baseline. Values were now in the control range in the putamen and reduced in the caudate nucleus (p < 0.05). The clinical score at "off" had significantly worsened (p < 0.0005) compared with the first PET scan. The nine PD patients reported here had already been investigated 3-4 months after therapy began and that time did not show a reduction of the initially increased RACLO binding capacity (data published previously). These results indicate long-term downregulation of striatal dopamine D2 receptor binding in PD. Receptor changes in the striatum of patients with PD may be induced by chronic dopaminergic therapy or occur independently of treatment, as a result of structural adaptation of the postsynaptic dopaminergic system to the progressive decline of nigrostriatal neurons.301Rinne, J. O.; Laihinen, A.; Ruottinen, H.; Ruotsalainen, U.; Någren, K.; Lehikoinen, P.; Oikonen, V.; Rinne, U. K. Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson’s disease: A PET study with [11C]raclopride. J. Neurol. Sci. 1995, 132, 156– 161, DOI: 10.1016/0022-510X(95)00137-Q[Crossref], [PubMed], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXptlWqtb0%253D&md5=009715926a74d89c62ad1bcc8bd99bf6Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease: A PET study with [11C]racloprideRinne, Juha O.; Laihinen, Arto; Ruottinen, Hanna; Ruotsalainen, Ulla; Nagren, Kjell; Pertti, Lehikoinen; Oikonen, Vesa; Rinne, U. K.Journal of the Neurological Sciences (1995), 132 (2), 156-61CODEN: JNSCAG; ISSN:0022-510X. (Elsevier)Striatal dopamine D2 receptors were studied, using positron emission tomog. (PET), in 10 patients with early Parkinson's disease without any antiparkinsonian medication and in 14 healthy controls. [11C]Raclopride was used as ligand and an equil. method was applied. The max. count of receptors (Bmax) and their dissocn. const. (Kd) were calcd. according to the Scatchard principle. In parkinsonian patients, the Bmax of D2 receptors was increased in the putamen contralateral to the predominant symptoms, as compared to the opposite putamen, by 33% (p = 0.0008). In the caudate nucleus no significant side to side differences was noted. On comparison with age-matched healthy controls, Bmax values in the putamen (p = 0.0012) but not in the caudate nucleus contralateral to the side of predominant clin. symptoms were increased in PD patients. The Kd values were unchanged. The difference in putaminal Bmax values between the opposite hemispheres correlated with the difference in the severity of parkinsonian motor symptoms between the two body sides (r = 0.69, p = 0.03). The present results show that there is both a relative and abs. increase in the no. of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease.302Payer, D. E.; Guttman, M.; Kish, S. J.; Tong, J.; Adams, J. R.; Rusjan, P.; Houle, S.; Furukawa, Y.; Wilson, A. A.; Boileau, I. D3 Dopamine receptor-preferring [11C]PHNO PET imaging in Parkinson patients with dyskinesia. Neurology 2016, 86, 224– 230, DOI: 10.1212/WNL.0000000000002285[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVGrt7Y%253D&md5=88822dc788366e98ec232ab0571a9c4eD3 dopamine receptor-preferring [11C]PHNO PET imaging in Parkinson patients with dyskinesiaPayer, Doris E.; Guttman, Mark; Kish, Stephen J.; Tong, Junchao; Adams, John R.; Rusjan, Pablo; Houle, Sylvain; Furukawa, Yoshiaki; Wilson, Alan A.; Boileau, IsabelleNeurology (2016), 86 (3), 224-230CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)To investigate whether levodopa-induced dyskinesias (LID) are assocd. with D3 overexpression in levodopa-treated humans with Parkinson disease (PD). In this case-control study, we used PET with the D3-preferring radioligand [11C]-(+)-PHNO to est. D2/3 receptor binding in patients with levodopa-treated PD with LID (n = 12) and without LID (n = 12), and healthy control subjects matched for age, sex, education, and mental status (n = 18). Compared to nondyskinetic patients, those with LID showed heightened [11C]-(+)-PHNO binding in the D3-rich globus pallidus. Both PD groups also showed higher binding than controls in the sensorimotor division of the striatum. In contrast, D2/3 binding in the ventral striatum was lower in patients with LID than without, possibly reflecting higher dopamine levels. Dopaminergic abnormalities contributing to LID may include elevated D2/3 binding in globus pallidus, perhaps reflecting D3 receptor upregulation. The findings support therapeutic strategies that target and diminish activity at D3 to prevent LID.303Seeman, P.; Wilson, A.; Gmeiner, P.; Kapur, S. Dopamine D2 and D3 receptors in human putamen, caudate nucleus, and globus pallidus. Synapse 2006, 60, 205– 211, DOI: 10.1002/syn.20298[Crossref], [PubMed], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvVGqsrg%253D&md5=1fb2b450e181d859c03256b8fa9f226cDopamine D2 and D3 receptors in human putamen, caudate nucleus, and globus pallidusSeeman, Philip; Wilson, Alan; Gmeiner, Peter; Kapur, ShitijSynapse (Hoboken, NJ, United States) (2006), 60 (3), 205-211CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)Because radioactive raclopride and radioactive (+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) are used to image dopamine (DA) D2 and D3 receptors in the striatum and globus pallidus in humans, the present study examd. the proportions of D2 and D3 receptors in postmortem tissues from these regions. Conflicting results were obtained when using a single concn. of remoxipride to occlude D2 receptors or using a single concn. of U99194A or FAUC 365 to occlude D3 receptors. However, using a range of concns. of FAUC 365, a D3-selective antagonist, to inhibit the binding [3H]raclopride or [3H]-(+)-PHNO to D3 receptors at low concns. (1-10 nM) and to inhibit ligand binding to D2 receptors at higher concns. (100-2000 nM), it was possible to measure the proportion of D2 and D3 receptors in the tissues. This method revealed that these 2 radioligands detected only D2 receptors in the dorsal putamen and the dorsal caudate nucleus, but detected a mixed population of 67% D2 and 33% D3 DA receptors in the ventral putamen, ventral caudate, and globus pallidus. The present findings are in good agreement with the known gene expression data for D2 and D3 receptors in these human brain regions.304Tziortzi, A. C.; Searle, G. E.; Tzimopoulou, S.; Salinas, C.; Beaver, J. D.; Jenkinson, M.; Laruelle, M.; Rabiner, E. A.; Gunn, R. N. Imaging dopamine receptors in humans with [11C]-(+)-PHNO: Dissection of D3 signal and anatomy. NeuroImage 2011, 54, 264– 277, DOI: 10.1016/j.neuroimage.2010.06.044[Crossref], [PubMed], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlCjsrnE&md5=59808003a4dad72b2f4f1c04b411c681Imaging dopamine receptors in humans with [11C]-(+)-PHNO: Dissection of D3 signal and anatomyTziortzi, Andri C.; Searle, Graham E.; Tzimopoulou, Sofia; Salinas, Cristian; Beaver, John D.; Jenkinson, Mark; Laruelle, Marc; Rabiner, Eugenii A.; Gunn, Roger N.NeuroImage (2011), 54 (1), 264-277CODEN: NEIMEF; ISSN:1053-8119. (Elsevier B.V.)[11C]-(+)-PHNO is a D3 preferring PET radioligand which has recently opened the possibility of imaging D3 receptors in the human brain in vivo. This imaging tool allows characterization of the distribution of D3 receptors in vivo and further investigation of their functional role. The specific [11C]-(+)-PHNO signal is a mixt. of D3 and D2 components with the relative magnitude of each component detd. by the regional receptor densities. An accurate and reproducible delineation of regions of interest (ROI) is therefore important for optimal anal. of human PET data. We present a set of anatomical guidelines for the delineation of D3 relevant ROIs including substantia nigra, hypothalamus, ventral pallidum/substantia innominata, ventral striatum, globus pallidus and thalamus. Delineation of these structures using this approach allowed for high intra- and inter-operator reproducibility. Subsequently we used a selective D3 antagonist to dissect the total [11C]-(+)-PHNO signal in each region into its D3 and D2 components and estd. the regional fraction of the D3 signal (f PHNO D3). In descending order of magnitude the following results for the f PHNO D3 were obtained: hypothalamus = 100%, substantia nigra = 100%, ventral pallidum/substantia innominata = 75%, globus pallidus = 65%, thalamus = 43%, ventral striatum = 26% and precommissural-ventral putamen = 6%. An automated approach for the delineation of these anatomical regions of interest was also developed and investigated in terms of its reproducibility and accuracy.305Payer, D. E.; Guttman, M.; Kish, S. J.; Tong, J.; Strafella, A.; Zack, M.; Adams, J. R.; Rusjan, P.; Houle, S.; Furukawa, Y.; Wilson, A. A.; Boileau, I. [11C]-(+)-PHNO PET imaging of dopamine D 2/3 receptors in Parkinson’s disease with impulse control disorders: [11C]PHNO binding in Parkinson’s disease. Mov. Disord. 2015, 30, 160– 166, DOI: 10.1002/mds.26135[Crossref], [PubMed], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit12rsLY%253D&md5=72a4e1ce35341c4ce8c0b35a12fec7d4[11C]-(+)-PHNO PET imaging of dopamine D2/3 receptors in Parkinson's disease with impulse control disordersPayer, Doris E.; Guttman, Mark; Kish, Stephen J.; Tong, Junchao; Strafella, Antonio; Zack, Martin; Adams, John R.; Rusjan, Pablo; Houle, Sylvain; Furukawa, Yoshiaki; Wilson, Alan A.; Boileau, IsabelleMovement Disorders (2015), 30 (2), 160-166CODEN: MOVDEA; ISSN:0885-3185. (Wiley-Blackwell)Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been assocd. with pathol. behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are assocd. with greater D3 dopamine receptor availability. We used positron emission tomog. (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [11C]-(+)-PHNO binding in D3-rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [11C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [11C]-(+)-PHNO binding is assocd. with D2 receptor levels, [11C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved. © 2015 International Parkinson and Movement Disorder Society.306Martinez, D.; Greene, K.; Broft, A.; Kumar, D.; Liu, F.; Narendran, R.; Slifstein, M.; Van Heertum, R.; Kleber, H. D. Lower level of endogenous dopamine in patients with cocaine dependence: Findings from PET imaging of D2/D3 receptors following acute dopamine depletion. Am. J. Psychiatry 2009, 166, 1170– 1177, DOI: 10.1176/appi.ajp.2009.08121801[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnmtFGisw%253D%253D&md5=6729c7b4fb2bfa296919785a6ed633e9Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletionMartinez Diana; Greene Kaitlin; Broft Allegra; Kumar Dileep; Liu Fei; Narendran Rajesh; Slifstein Mark; Van Heertum Ronald; Kleber Herbert DThe American journal of psychiatry (2009), 166 (10), 1170-7 ISSN:.OBJECTIVE: Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D(2)/D(3)) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D(2)/D(3) receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects. METHOD: Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [(11)C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole. RESULTS: Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [(11)C]raclopride binding following AMPT administration. The increase in [(11)C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum. CONCLUSIONS: The decrease in striatal D(2)/D(3 )receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.307Martinez, D.; Narendran, R. Imaging Neurotransmitter Release by Drugs of Abuse. In Behavioral Neuroscience of Drug Addiction; Self, D. W., Staley Gottschalk, J. K., Eds.; Current Topics in Behavioral Neurosciences; Springer: Berlin, Heidelberg, 2010; Vol. 3, pp 219– 245.308Fowler, J.; MacGregor, R.; Wolf, A.; Arnett, C.; Dewey, S.; Schlyer, D.; Christman, D.; Logan, J.; Smith, M.; Sachs, H. Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science 1987, 235, 481– 485, DOI: 10.1126/science.3099392[Crossref], [PubMed], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXhtlCis7s%253D&md5=ade47b744d08e5ce8f34664d96455a8eMapping human brain monoamine oxidase A and B with carbon-11-labeled suicide inactivators and PETFowler, J. S.; MacGregor, R. R.; Wolf, A. P.; Arnett, C. D.; Dewey, S. L.; Schlyer, D.; Christman, D.; Logan, J.; Smith, M.; et al.Science (Washington, DC, United States) (1987), 235 (4787), 481-5CODEN: SCIEAS; ISSN:0036-8075.The regional distribution of MAO types A and B were identified in human brain in vivo with i.v. injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and position emission tomog. (PET). The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in 1 subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.309Vuorimaa, A.; Rissanen, E.; Airas, L. In vivo PET imaging of adenosine 2A receptors in neuroinflammatory and neurodegenerative disease. Contrast Media Mol. Imaging 2017, 2017, 6975841, DOI: 10.1155/2017/6975841[Crossref], [PubMed], [CAS], Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvitF2ksg%253D%253D&md5=3c37afa18a3c2b0ef7b0aaaf36786200In Vivo PET Imaging of Adenosine 2A Receptors in Neuroinflammatory and Neurodegenerative DiseaseVuorimaa Anna; Rissanen Eero; Airas Laura; Vuorimaa Anna; Rissanen Eero; Airas LauraContrast media & molecular imaging (2017), 2017 (), 6975841 ISSN:.Adenosine receptors are G-protein coupled P1 purinergic receptors that are broadly expressed in the peripheral immune system, vasculature, and the central nervous system (CNS). Within the immune system, adenosine 2A (A2A) receptor-mediated signaling exerts a suppressive effect on ongoing inflammation. In healthy CNS, A2A receptors are expressed mainly within the neurons of the basal ganglia. Alterations in A2A receptor function and expression have been noted in movement disorders, and in Parkinson's disease pharmacological A2A receptor antagonism leads to diminished motor symptoms. Although A2A receptors are expressed only at a low level in the healthy CNS outside striatum, pathological challenge or inflammation has been shown to lead to upregulation of A2A receptors in extrastriatal CNS tissue, and this has been successfully quantitated using in vivo positron emission tomography (PET) imaging and A2A receptor-binding radioligands. Several radioligands for PET imaging of A2A receptors have been developed in recent years, and A2A receptor-targeting PET imaging may thus provide a potential additional tool to evaluate various aspects of neuroinflammation in vivo. This review article provides a brief overview of A2A receptors in healthy brain and in a selection of most important neurological diseases and describes the recent advances in A2A receptor-targeting PET imaging studies.310Cybulska, K.; Perk, L.; Booij, J.; Laverman, P.; Rijpkema, M. Huntington’s disease: A review of the known PET imaging biomarkers and targeting radiotracers. Molecules 2020, 25, 482, DOI: 10.3390/molecules25030482[Crossref], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXktVOjsrY%253D&md5=89ec0a3ecbf952f3e9e035e50e8e4180Huntington's disease: a review of the known PET imaging biomarkers and targeting radiotracersCybulska, Klaudia; Perk, Lars; Booij, Jan; Laverman, Peter; Rijpkema, MarkMolecules (2020), 25 (3), 482CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomog. (PET) studies relating to HD was performed, including clin. and preclin. data. PET is a powerful tool for visualisation of the HD pathol. by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed mol. snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognize particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochem. picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.311Ishiwata, K.; Ogi, N.; Hayakawa, N.; Oda, K.; Nagaoka, T.; Toyama, H.; Suzuki, F.; Endo, K.; Tanaka, A.; Senda, M. Adenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: Comparison with the dopamine receptor imaging. Ann. Nucl. Med. 2002, 16, 467– 475, DOI: 10.1007/BF02988643[Crossref], [PubMed], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnvFKisA%253D%253D&md5=95b207f690f7a3cefb32f8bdf8dd98cbAdenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: comparison with the dopamine receptor imagingIshiwata, Kiichi; Ogi, Nobuo; Hayakawa, Nobutaka; Oda, Keiichi; Nagaoka, Tsukasa; Toyama, Hinako; Suzuki, Fumio; Endo, Kazutoyo; Tanaka, Akira; Senda, MichioAnnals of Nuclear Medicine (2002), 16 (7), 467-475CODEN: ANMEEX; ISSN:0914-7187. (Japanese Society of Nuclear Medicine)We proposed [11C]KF18446 as a selective radioligand for mapping the adenosine A2A receptors being highly enriched in the striatum by positron emission tomog. (PET). In the present study, we investigated whether [11C]KF18446 PET can detect the change in the striatal adenosine A2A receptors in the rat after unilateral injection of an excitotoxin quinolinic acid into the striatum, a Huntington's disease model, to demonstrate the usefulness of [11C]KF18446. The extent of the striatal lesion was identified based on MRI, to which the PET was co-registered. The binding potential of [11C]KF18446 significantly decreased in the quinolinic acid-lesioned striatum. The decrease was comparable to the decrease in the potential of [11C]raclopride binding to dopamine D2 receptors in the lesioned striatum, but seemed to be larger than the decrease in the potential of [11C]SCH 23390 binding to dopamine D1 receptors. Ex vivo and in vitro autoradiog. validated the PET signals. We concluded that [11C]KF18446 PET can detect change in the adenosine A2A receptors in the rat model, and will provide a new diagnostic tool for characterizing post-synaptic striatopallidal neurons in the striatum.312Ishiwata, K.; Noguchi, J.; Wakabayashi, S.; Shimada, J.; Ogi, N.; Nariai, T.; Tanaka, A.; Endo, K.; Suzuki, F.; Senda, M. 11C-labeled KF18446: A potential central nervous system adenosine A2a receptor ligand. J. Nucl. Med. 2000, 41, 345– 354[PubMed], [CAS], Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhtlGnt7w%253D&md5=3a0baaa69c597e511b4901d99d17da1211C-labeled KF18446: a potential central nervous system adenosine A2a receptor ligandIshiwata, Kiichi; Noguchi, Junko; Wakabayashi, Shin-Ichi; Shimada, Junichi; Ogi, Nobuo; Nariai, Tadashi; Tanaka, Akira; Endo, Kazutoyo; Suzuki, Fumio; Senda, MichioJournal of Nuclear Medicine (2000), 41 (2), 345-354CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine, Inc.)To develop PET ligands for mapping central nervous system (CNS) adenosine A2a receptors that are localized in the striatum and are coupled with dopamine receptors, 3 11C-labeled xanthine-type adenosine A2a antagonists, [11C]KF18446 ([7-methyl-11C]-(E) -8-(3,4,5-trimethoxystyryl)-1,3,7- trimethylxanthine), [11C]KF19631 ([7-methyl-11C]- (E)-1,3-diallyl-7-methyl-8- (3,4,5- trimethoxystyryl-)xanthine), and [11C]CSC ([7-methyl-11C] -8-chlorostyrylcaffeine), were compared with [11C]KF17837 ([7-methyl-11C]- (E)-8-(3,4-dimethoxystyryl) -1,3-dipropyl-7- methylxanthine). The regional brain uptake of the tracers, the effect of the coinjected adenosine antagonists on the uptake, and the metab. were studied in mice. In rats, the regional brain uptake of the tracers was visualized by ex vivo autoradiog. (ARG). The A2a receptor binding of antagonist 1 was also measured by in vitro ARG. Imaging of the monkey brain was performed with PET with antagonist 1. In mice, the highest striatal uptake was found for antagonist 1 followed by antagonists 2 and 4. The uptake was inhibited by each of 3 KF compds. and by CSC, but not by an A1 antagonist KF15372. Another selective nonxanthine-type A2a antagonist SCH 58261 significantly decreased the striatal uptake of only antagonist 1, the labeled metabolites of which were less than 20% in the plasma 30 min postinjection, but were negligible in the brain tissue. In ex vivo ARG, antagonist 1 showed the highest striatal uptake and the highest uptake ratio of the striatum to the other brain regions. A high and selective binding of antagonist 1 to the striatum was also confirmed by in vitro ARG. PET with antagonist 1 visualized adenosine A2a receptors in the monkey striatum. These results indicate that antagonist 1 ([11C]KF18446) is the most suitable PET ligand for mapping adenosine A2a receptors in the CNS.313Paul, S.; Khanapur, S.; Sijbesma, J. W.; Ishiwata, K.; Elsinga, P. H.; Meerlo, P.; Dierckx, R. A.; van Waarde, A. Use of 11C-MPDX and PET to study adenosine A1 receptor occupancy by nonradioactive agonists and antagonists. J. Nucl. Med. 2014, 55, 315– 320, DOI: 10.2967/jnumed.113.130294[Crossref], [PubMed], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltlaqtLk%253D&md5=097d76539235c631097340fc4a9915faUse of 11C-MPDX and PET to study adenosine A1 receptor occupancy by nonradioactive agonists and antagonistsPaul, Soumen; Khanapur, Shivashankar; Sijbesma, Jurgen W.; Ishiwata, Kiichi; Elsinga, Philip H.; Meerlo, Peter; Dierckx, Rudi A.; van Waarde, ArenJournal of Nuclear Medicine (2014), 55 (2), 315-320CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)Adenosine A1 receptors (A1Rs) in human and rodent brains can be visualized with the radioligand 8-dicyclopropylmethyl-1-11C-methyl-3-propylxanthine (11C-MPDX) and PET. Here we investigated whether A1R occupancy by nonradioactive agonists and antagonists can be assessed with this technique. Methods: Small-animal PET scans with arterial blood sampling were obtained for 4 groups of isoflurane-anesthetized Wistar rats: controls (n = 7); pretreated with a centrally active A1R agonist, N6-cyclopentyladenosine (CPA; 0.25 mg/kg i.p.; dissocn. const., 0.48 nM; n = 7); pretreated with a moderate dose of caffeine (antagonist for A1Rs and adenosine A2A receptors; 4 mg/kg i.p.; dissocn. const., 11 μM; n = 6); and pretreated with a high dose of caffeine (40 mg/kg i.p.; n = 6). Results: The administration of CPA resulted in a strong redn. (>50%) in the heart rate, and caffeine administration resulted in a small increase (10%-15%). A caffeine dose of 4 mg/kg (n = 6) resulted in 65.9% A1R occupancy, and a dose of 40 mg/kg (n = 6) resulted in 98.5% occupancy (calcd. from a modified Lassen plot). However, the administration of CPA resulted in an increase in 11C-MPDX binding in the brain. Conclusion: Small-animal PET with 11C-MPDX can be used to assess antagonist but not agonist binding at A1Rs. Changes in tracer uptake after the administration of CPA resembled previously reported changes induced by treatment of rats with ethanol and an adenosine kinase inhibitor (ABT702). Thus, the administration of an exogenous agonist or increasing the level of an endogenous agonist have similar effects. Agonists and antagonists may bind to different sites on the A1R protein having allosteric interactions.314Hayashi, S.; Inaji, M.; Nariai, T.; Oda, K.; Sakata, M.; Toyohara, J.; Ishii, K.; Ishiwata, K.; Maehara, T. Increased binding potential of brain adenosine A 1 receptor in chronic stages of patients with diffuse axonal injury measured with [1-methyl- 11C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine positron emission tomography imaging. Journal of Neurotrauma. 2018, 35, 25– 31, DOI: 10.1089/neu.2017.5006[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cjps1Wrtw%253D%253D&md5=eae75f47be1869083490310c4b7ab8caIncreased Binding Potential of Brain Adenosine A1 Receptor in Chronic Stages of Patients with Diffuse Axonal Injury Measured with [1-methyl-(11)C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine Positron Emission Tomography ImagingHayashi Shihori; Inaji Motoki; Nariai Tadashi; Maehara Taketoshi; Oda Keiichi; Sakata Muneyuki; Toyohara Jun; Ishii Kenji; Ishiwata Kiichi; Ishiwata Kiichi; Ishiwata KiichiJournal of neurotrauma (2018), 35 (1), 25-31 ISSN:.The positron emission tomography (PET) radioligand for adenosine A1 receptor (A1R) [1-methyl-(11)C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX) has recently been developed for human brain imaging. In the present study, we evaluated the alteration of the A1R in patients with diffuse axonal injury (DAI) in chronic stage in vivo. Ten patients with DAI (7 men and 3 women) were included in this study. Three PET examinations were sequentially performed to measure A1R binding with (11)C-MPDX, glucose metabolism with (18)F-fluorodeoxyglucose (FDG), and central benzodiazepine receptor binding with (11)C-flumazenil (FMZ), and decreases of (11)C-FMZ uptake indicate neuronal loss. (11)C- MPDX did not depict any lesion with significantly decreased nondisplaceable binding potential (BPND) in comparison to healthy controls (14 men) in region of interest (ROI) analysis. Instead, it showed a significant increase of BPND in the lower frontal and posterior cingulate cortexes and rolandic area (p < 0.05) in ROI analysis. In (18)F-FDG PET, the standardized uptake values (SUVs) ratio to the whole brain were decreased in anterior and posterior cingulate gyrus compared to controls (14 men and 9 women; p < 0.01). In (11)C-FMZ PET, the SUV ratio to the cerebellum was decreased in anterior cingulate gyrus in ROI analysis (controls, 9 men and 6 women; p < 0.01). The area with significantly increased (11)C-MPDX binding, lower frontal cortex, rolandic area, and posterior cingulate gyrus, did not overlap with the areas of neuronal loss detected by decreased (11)C-FMZ binding and did not completely overlap with area of reduced(18)F-FDG uptake. We obtained the first (11)C-MPDX PET images reflecting the A1R BPND in human DAI brain in vivo. (11)C-MPDX depicted increased A1R BPND in the areas surrounding the injured brain, whereas (18)F-FDG demonstrated reduction throughout the brain. The results suggested that A1R might continuously confer neuroprotective or neuromodulatory effects in DAI even in the chronic stage.315Mishina, M.; Ishii, K.; Kimura, Y.; Suzuki, M.; Kitamura, S.; Ishibashi, K.; Sakata, M.; Oda, K.; Kobayashi, S.; Kimura, K.; Ishiwata, K. Adenosine A 1 receptors measured with 11 C-MPDX PET in early Parkinson’s disease. Synapse 2017, 71, e21979 DOI: 10.1002/syn.21979316Lahesmaa, M.; Oikonen, V.; Helin, S.; Luoto, P.; U Din, M.; Pfeifer, A.; Nuutila, P.; Virtanen, K. A. Regulation of human brown adipose tissue by adenosine and A2A receptors – studies with [15O]H2O and [11C]TMSX PET/CT. Eur. J. Nucl. Med. Mol. Imaging 2019, 46, 743– 750, DOI: 10.1007/s00259-018-4120-2[Crossref], [PubMed], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFSqtLjP&md5=bd7eb3664279f1ebd18ed7afc669f64aRegulation of human brown adipose tissue by adenosine and A2A receptors - studies with [15O]H2O and [11C]TMSX PET/CTLahesmaa, Minna; Oikonen, Vesa; Helin, Semi; Luoto, Pauliina; U Din, Mueez; Pfeifer, Alexander; Nuutila, Pirjo; Virtanen, Kirsi A.European Journal of Nuclear Medicine and Molecular Imaging (2019), 46 (3), 743-750CODEN: EJNMA6; ISSN:1619-7070. (Springer)Brown adipose tissue (BAT) has emerged as a potential target to combat obesity and diabetes, but novel strategies to activate BAT are needed. Adenosine and A2A receptor (A2AR) agonism activate BAT in rodents, and endogenous adenosine is released locally in BAT as a byproduct of noradrenaline, but physiol. data from humans is lacking. The purpose of this pilot study was to investigate the effects of exogenous adenosine on human BAT perfusion, and to det. the d. of A2ARs in human BAT in vivo for the first time, using PET/CT imaging. Healthy, lean men (n = 10) participated in PET/CT imaging with two radioligands. Perfusion of BAT, white adipose tissue (WAT) and muscle was quantified with [15O]H2O at baseline, during cold exposure and during i.v. administration of adenosine. A2AR d. of the tissues was quantified with [11C]TMSX at baseline and during cold exposure. Adenosine increased the perfusion of BAT even more than cold exposure (baseline 8.3 ± 4.5, cold 19.6 ± 9.3, adenosine 28.6 ± 7.9 μmol/100 g/min, p < 0.01). Distribution vol. of [11C]TMSX in BAT was significantly lower during cold exposure compared to baseline. In cold, low [11C]TMSX binding coincided with high concns. of noradrenaline. Adenosine administration caused a maximal perfusion effect in human supraclavicular BAT, indicating increased oxidative metab. Cold exposure increased noradrenaline concns. and decreased the d. of A2AR available for radioligand binding in BAT, suggesting augmented release of endogenous adenosine. Our results show that adenosine and A2AR are relevant for activation of human BAT, and A2AR provides a future target for enhancing BAT metab.317Zhou, X.; Khanapur, S.; Huizing, A. P.; Zijlma, R.; Schepers, M.; Dierckx, R. A. J. O.; van Waarde, A.; de Vries, E. F. J.; Elsinga, P. H. Synthesis and preclinical evaluation of 2-(2-furanyl)-7-[2-[4-[4-(2-[11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e ][1,2,4]triazolo[1,5- c ]pyrimidine-5-amine ([11C]preladenant) as a PET tracer for the imaging of cerebral adenosine A 2A receptors. J. Med. Chem. 2014, 57, 9204– 9210, DOI: 10.1021/jm501065t[ACS Full Text], [CAS], Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1OktLfM&md5=eef1c94bbc68e8bc456de136d5bd334eSynthesis and Preclinical Evaluation of 2-(2-Furanyl)-7-[2-[4-[4-(2-[11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine ([11C]Preladenant) as a PET Tracer for the Imaging of Cerebral Adenosine A2A ReceptorsZhou, Xiaoyun; Khanapur, Shivashankar; Huizing, Anja P.; Zijlma, Rolf; Schepers, Marianne; Dierckx, Rudi A. J. O.; van Waarde, Aren; de Vries, Erik F. J.; Elsinga, Philip H.Journal of Medicinal Chemistry (2014), 57 (21), 9204-9210CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)2-(2-Furanyl)-7-[2-[4-[4-(2-[11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine [11C]-3 ([11C]Preladenant) was developed for mapping cerebral adenosine A2A receptors (A2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD), and in vitro autoradiog. (ARG) expts. Regional brain uptake of [11C]-3 was consistent with known A2ARs distribution, with highest uptake in striatum. The results indicate that [11C]-3 has favorable brain kinetics and exhibits suitable characteristics as an A2AR PET tracer.318Zhou, X.; Elsinga, P. H.; Khanapur, S.; Dierckx, R. A. J. O.; de Vries, E. F. J.; de Jong, J. R. Radiation dosimetry of a novel adenosine A2A receptor radioligand [11C]preladenant based on PET/CT imaging and ex vivo biodistribution in rats. Mol. Imaging Biol. 2017, 19, 289– 297, DOI: 10.1007/s11307-016-0992-3[Crossref], [PubMed], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVSlsr3O&md5=667c9b52dbfd01da31b92b34147b22dfRadiation Dosimetry of a Novel Adenosine A2A Receptor Radioligand [11C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in RatsZhou, Xiaoyun; Elsinga, Philip H.; Khanapur, Shivashankar; Dierckx, Rudi A. J. O.; de Vries, Erik F. J.; de Jong, Johan R.Molecular Imaging and Biology (2017), 19 (2), 289-297CODEN: MIBOCZ; ISSN:1860-2002. (Springer)Purpose: [11C]Preladenant was developed as a novel adenosine A2A receptor PET radioligand. The aim of this study was to det. the radiation dosimetry of [11C]preladenant and to investigate whether dosimetry estn. based on organ harvesting can be replaced by positron emission tomog. (PET)/x-ray computed tomog. (CT) imaging in rats. Procedures: Male Wistar rats (n = 35) were i.v. injected with [11C]preladenant. The tracer biodistribution was detd. by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty vols. of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical ref. The dynamic time-activity curves were used to calc. organ residence times (RTs). Human radiation dosimetry ests., derived from rat data, were calcd. with OLINDA/EXM 1.1. Results: PET-imaging and organ-harvesting estd. comparable organ RTs, with differences of 6-27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, resp. The crit. organ was the small intestine with a dose of 25 μSv/MBq. The EDs (EDs) calcd. from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 μSv/MBq, resp., using the International Commission on Radiol. Protection 60 tissue weighting factors. Conclusions: The ED of [11C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estn. of the radiation dosimetry of [11C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the no. of lab. animals required.319Elmenhorst, D.; Kroll, T.; Wedekind, F.; Weisshaupt, A.; Beer, S.; Bauer, A. In vivo kinetic and steady-state quantification of 18F-CPFPX binding to rat cerebral A1 adenosine receptors: Validation by displacement and autoradiographic experiments. J. Nucl. Med. 2013, 54, 1411– 1419, DOI: 10.2967/jnumed.112.115576[Crossref], [PubMed], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVejsr7J&md5=e411324166cbb6e6ed5c655dd2ca5d8aIn vivo kinetic and steady-state quantification of 18F-CPFPX binding to rat cerebral A1 adenosine receptors: validation by displacement and autoradiographic experimentsElmenhorst, David; Kroll, Tina; Wedekind, Franziska; Weisshaupt, Angela; Beer, Simone; Bauer, AndreasJournal of Nuclear Medicine (2013), 54 (8), 1411-1419CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)In vivo imaging of the A1 adenosine receptor (A1AR) using 18F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (18F-CPFPX) and PET has become an important tool for studying physiol. and pathol. states of the human brain. However, dedicated exptl. settings for small-animal studies are still lacking. The aim of the present study was therefore to develop and evaluate suitable pharmacokinetic models for the quantification of the cerebral A1AR in high-resoln. PET. Methods: On a dedicated animal PET scanner, 15 rats underwent 18F-CPFPX PET scans of 120-min duration. In all animals, arterial blood samples were drawn and cor. for metabolites. The radioligand was injected either as a bolus or as a bolus plus const. infusion. For the definition of unspecific binding, the A1AR selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was applied. After PET, the brains of 9 animals were dissected and in vitro satn. binding was performed using high-resoln. 3H-DPCPX autoradiog. Results: The kinetics of 18F-CPFPX were well described by either compartmental or noncompartmental models based on arterial input function. The resulting distribution vol. ratio correlated with a low bias toward identity with the binding potential derived from a ref. region (olfactory bulb) approach. Furthermore, PET quantification correlated significantly with autoradiog. in vitro data. Blockade of the A1AR with DPCPX identified specific binding of about 45% in the ref. region olfactory bulb. Conclusion: The present study provides evidence that 18F-CPFPX PET based on a ref. tissue approach can be performed quant. in rodents in selected applications. Specific binding in the ref. region needs careful consideration for quant. investigations.320Kreft, S.; Bier, D.; Holschbach, M. H.; Schulze, A.; Coenen, H. H. New potent A1 adenosine receptor radioligands for positron emission tomography. Nucl. Med. Biol. 2017, 44, 69– 77, DOI: 10.1016/j.nucmedbio.2016.09.004[Crossref], [PubMed], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVSntL%252FL&md5=4cfb2a1568f9a31da4578b92d1147739New potent A1 adenosine receptor radioligands for positron emission tomographyKreft, Sabrina; Bier, Dirk; Holschbach, Marcus H.; Schulze, Annette; Coenen, Heinz H.Nuclear Medicine and Biology (2017), 44 (), 69-77CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is meanwhile an accepted receptor ligand to examine the A1 adenosine receptor (A1AR) in humans by positron emission tomog. (PET). A major drawback of this compd. is its rather fast metabolic degrdn. in vivo. Therefore two new xanthine derivs., namely 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (CBCPM; 5) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (CPMMCB; 6) were designed and synthesized as potential alternatives to CPFPX. In membrane binding studies both compds. showed nanomolar affinity for the A1AR. In vitro autoradiog. studies of [18F]5 and [18F]6, using rat brain slices, showed the expected accumulation in regions known to have a high adenosine A1 receptor expression while exhibiting the necessary low unspecific binding. However, in vitro metabolite studies using human liver microsomes revealed a comparable metabolic degrdn. rate for both new xanthine derivs. and CPFPX.321Lindemann, M.; Hinz, S.; Deuther-Conrad, W.; Namasivayam, V.; Dukic-Stefanovic, S.; Teodoro, R.; Toussaint, M.; Kranz, M.; Juhl, C.; Steinbach, J.; Brust, P.; Müller, C. E.; Wenzel, B. Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptor. Bioorg. Med. Chem. 2018, 26, 4650– 4663, DOI: 10.1016/j.bmc.2018.07.045[Crossref], [PubMed], [CAS], Google Scholar321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsV2lurzP&md5=9cfeb12865ae0af6f1a1f87144d4e2c9Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptorLindemann, Marcel; Hinz, Sonja; Deuther-Conrad, Winnie; Namasivayam, Vigneshwaran; Dukic-Stefanovic, Sladjana; Teodoro, Rodrigo; Toussaint, Magali; Kranz, Mathias; Juhl, Cathleen; Steinbach, Joerg; Brust, Peter; Mueller, Christa E.; Wenzel, BarbaraBioorganic & Medicinal Chemistry (2018), 26 (16), 4650-4663CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)On the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a-c) were synthesized contg. a 2-fluoropyridine moiety suitable for 18F-labeling. Compd. 7a was docked into a homol. model of the A2B receptor based on X-ray structures of the related A2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were detd. at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A1 receptor, 7a was radiolabeled as the most suitable candidate (Ki(A2B) = 4.24 nM) in order to perform in vivo studies in mice with the aim to est. fundamental pharmacokinetic characteristics of the compd. class. Organ distribution studies and a single PET study demonstrated brain uptake of [18F]7a with a standardized uptake value (SUV) of ≈1 at 5 min post injection followed by a fast wash out. Metab. studies of [18F]7a in mice revealed the formation of a blood-brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivs. with improved binding properties and metabolic stability in vivo.322Niccolini, F.; Haider, S.; Reis Marques, T.; Muhlert, N.; Tziortzi, A. C.; Searle, G. E.; Natesan, S.; Piccini, P.; Kapur, S.; Rabiner, E. A.; Gunn, R. N.; Tabrizi, S. J.; Politis, M. Altered PDE10A expression detectable early before symptomatic onset in Huntington’s disease. Brain 2015, 138, 3016– 3029, DOI: 10.1093/brain/awv214[Crossref], [PubMed], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252Flt1KqtA%253D%253D&md5=35244382e3e08926abebd5ce93bb061bAltered PDE10A expression detectable early before symptomatic onset in Huntington's diseaseNiccolini Flavia; Politis Marios; Haider Salman; Tabrizi Sarah J; Reis Marques Tiago; Natesan Sridhar; Kapur Shitij; Muhlert Nils; Tziortzi Andri C; Searle Graham E; Piccini Paola; Rabiner Eugenii A; Gunn Roger NBrain : a journal of neurology (2015), 138 (Pt 10), 3016-29 ISSN:.There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.323Hebb, A. L. O.; Robertson, H. A.; Denovan-Wright, E. M. Striatal phosphodiesterase MRNA and protein levels are reduced in Huntington’s disease transgenic mice prior to the onset of motor symptoms. Neuroscience 2004, 123, 967– 981, DOI: 10.1016/j.neuroscience.2003.11.009[Crossref], [PubMed], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvFKgsg%253D%253D&md5=f274758b2f39ce57fae14cb76d61ff50Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington's disease transgenic mice prior to the onset of motor symptomsHebb, A. L. O.; Robertson, H. A.; Denovan-Wright, E. M.Neuroscience (Oxford, United Kingdom) (2004), 123 (4), 967-981CODEN: NRSCDN; ISSN:0306-4522. (Elsevier Science Ltd.)Inheritance of a single copy of the gene encoding huntingtin (HD) with an expanded polyglutamine-encoding CAG repeat leads to neuronal dysfunction, neurodegeneration and the development of the symptoms of Huntington's disease (HD). The authors have found that the steady-state mRNA levels of two members of the phosphodiesterase (PDE) multi-gene family decrease over time in the striatum of R6 transgenic HD mice relative to age-matched wild-type littermates. Phosphodiesterase 10A (PDE10A) mRNA and protein levels decline in the striatum of R6/1 and R6/2 HD mice prior to motor symptom development. The rate of redn. in PDE10A protein correlates with the rate of decline of the message and the decrease in PDE10A mRNA and protein is more rapid in R6/2 compared with R6/1 mice. Both PDE10A protein and mRNA, therefore, decline to min. levels prior to the onset of overt phys. symptoms in both strains of transgenic mice. Moreover, protein levels of PDE10A are decreased in the caudate-putamen of grade 3 HD patients compared with age-matched neuropathol. normal controls. Striatal PDE1B mRNA levels also decline in R6/1 and R6/2 HD mice; however, the decrease in striatal PDE10A levels (>60%) was greater than that obsd. for PDE1B and immediately preceded the onset of motor symptoms. In contrast, PDE4A mRNA levels are relatively low in the striatum and do not differ between age-matched wild-type and transgenic HD mice. This suggests that the regulation of PDE10A and PDE1B, but not PDE4A, mRNA levels is dependent on the relative expression of or no. of CAG repeats within the human HD transgene. The loss of phosphodiesterase activity may lead to dysregulation of cAMP and cGMP levels in the striatum, a region of the brain that contributes to the control of movement and cognition.324Tu, Z.; Xu, J.; Jones, L. A.; Li, S.; Mach, R. H. Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: Radiosynthesis, in vitro and in vivo evaluation. Nucl. Med. Biol. 2010, 37, 509– 516, DOI: 10.1016/j.nucmedbio.2009.12.012[Crossref], [PubMed], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlvVeju7o%253D&md5=4909a2ea1c548910efc84a2369b38416Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluationTu, Zhude; Xu, Jinbin; Jones, Lynne A.; Li, Shihong; Mach, Robert H.Nuclear Medicine and Biology (2010), 37 (4), 509-516CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase (PDE) 10A with IC50 values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiol. role of PDE10A. Here, we report the radiosynthesis of [11C]papaverine and the in vitro and in vivo evaluation of [11C]papaverine as a potential positron emission tomog. (PET) radiotracer for imaging PDE10A in the central nervous system (CNS). The radiosynthesis of papaverine with 11C was achieved by O-methylation of the corresponding des-Me precursor with [11C]methyl iodide. [11C]papaverine was obtained with ∼70% radiochem. yield and a specific activity >10 Ci/μmol. In vitro autoradiog. studies of rat and monkey brain sections revealed selective binding of [11C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [11C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. MicroPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [11C]papaverine from brain. Our initial evaluation suggests that despite papaverine's utility for in vitro studies and as a pharmaceutical tool, [11C]papaverine is not an ideal radioligand for clin. imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.325Liu, H.; Jin, H.; Yue, X.; Zhang, X.; Yang, H.; Li, J.; Flores, H.; Su, Y.; Perlmutter, J. S.; Tu, Z. Preclinical evaluation of a promising C-11 labeled PET tracer for imaging phosphodiesterase 10A in the brain of living subject. NeuroImage 2015, 121, 253– 262, DOI: 10.1016/j.neuroimage.2015.07.049[Crossref], [PubMed], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yhtbvJ&md5=09bcfb0fa42e4deaadc22344fdbf8061Preclinical evaluation of a promising C-11 labeled PET tracer for imaging phosphodiesterase 10A in the brain of living subjectLiu, Hui; Jin, Hongjun; Yue, Xuyi; Zhang, Xiang; Yang, Hao; Li, Junfeng; Flores, Hubert; Su, Yi; Perlmutter, Joel S.; Tu, ZhudeNeuroImage (2015), 121 (), 253-262CODEN: NEIMEF; ISSN:1053-8119. (Elsevier Inc.)Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling. A PET tracer for PDE10A may serve as a tool to evaluate PDE10A expression in vivo in central nervous system disorders with striatal pathol. Here, we further characterized the binding properties of a previously reported radioligand we developed for PDE10A, [11C]TZ1964B, in rodents and nonhuman primates (NHPs). The tritiated counterpart [3H]TZ1964B was used for in vitro binding characterizations in rat striatum homogenates and in vitro autoradiog. studies in rat brain slices. The carbon-11 labeled [11C]TZ1964B was utilized in the ex vivo autoradiog. studies for the brain of rats and microPET imaging studies for the brain of NHPs. MicroPET scans of [11C]TZ1964B in NHPs were conducted at baseline, as well as with using a selective PDE10A inhibitor MP-10 for either pretreatment or displacement. The in vivo regional target occupancy (Occ) was obtained by pretreating with different doses of MP-10 (0.05-2.00 mg/kg). Both in vitro binding assays and in vitro autoradiog. studies revealed a nanomolar binding affinity of [3H]TZ1964B to the rat striatum. The striatal binding of [3H]TZ1964B and [11C]TZ1964B was either displaced or blocked by MP-10 in rats and NHPs. Autoradiog. and microPET imaging confirmed that the specific binding of the radioligand was found in the striatum but not in the cerebellum. Blocking studies also confirmed the suitability of the cerebellum as an appropriate ref. region. The binding potentials (BPND) of [11C]TZ1964B in the NHP striatum that were calcd. using either the Logan ref. model (LoganREF, 3.96 ± 0.17) or the simplified ref. tissue model (SRTM, 4.64 ± 0.47), with the cerebellum as the ref. region, was high and had good reproducibility. The occupancy studies indicated a MP-10 dose of 0.31 ± 0.09 mg/kg (LoganREF)/0.45 ± 0.17 mg/kg (SRTM) occupies 50% striatal PDE10A binding sites. Studies in rats and NHPs demonstrated radiolabeled TZ1964B has a high binding affinity and good specificity for PDE10A, as well as favorable in vivo pharmacokinetic properties and binding profiles. Our data suggests that [11C]TZ1964B is a promising radioligand for in vivo imaging PDE10A in the brain of living subject.326Liu, H.; Jin, H.; Luo, Z.; Yue, X.; Zhang, X.; Flores, H.; Su, Y.; Perlmutter, J. S.; Tu, Z. In vivo characterization of two 18F-labeled PDE10A PET radioligands in nonhuman primate brains. ACS Chem. Neurosci. 2018, 9, 1066– 1073, DOI: 10.1021/acschemneuro.7b00458[ACS Full Text], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFOntb8%253D&md5=62dd91b34d4386004051c2809afa3899In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate BrainsLiu, Hui; Jin, Hongjun; Luo, Zonghua; Yue, Xuyi; Zhang, Xiang; Flores, Hubert; Su, Yi; Perlmutter, Joel S.; Tu, ZhudeACS Chemical Neuroscience (2018), 9 (5), 1066-1073CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Positron emission tomog. (PET) with phosphodiesterase 10A (PDE10A) specific radioligands provides a noninvasive and quant. imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. We recently reported two potent 18F-labeled PDE10A radioligands (18F-TZ19106B and 18F-TZ8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. Herein, we focused on in vivo characterization of 18F-TZ19106B and 18F-TZ8110 to identify a suitable radioligand for imaging PDE10A in vivo. We directly compared microPET studies of these two radiotracers in adult male Macaca fascicularis nonhuman primates (NHPs). 18F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than 18F-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BPND) estd. using ref.-based modeling anal. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of 18F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of 18F-TZ19106B binding to varying no. of specific binding sites using escalating doses of MP-10 blockade (0.3, 0.5, 1.0, 1.5, and 2.0 mg/kg). Pretreatment with a dopamine D2-like receptor antagonist enhanced the striatal uptake of 18F-TZ19106B. Our results indicate that 18F-TZ19106B is a promising radioligand candidate for imaging PDE10A in vivo and it may be used to det. target engagement of PDE10A inhibitors and serve as a tool to evaluate the effect of novel antipsychotic therapies.327Li, J.; Zhang, X.; Jin, H.; Fan, J.; Flores, H.; Perlmutter, J. S.; Tu, Z. Synthesis of fluorine-containing phosphodiesterase 10A (PDE10A) inhibitors and the in vivo evaluation of F-18 labeled PDE10A PET tracers in rodent and nonhuman primate. J. Med. Chem. 2015, 58, 8584– 8600, DOI: 10.1021/acs.jmedchem.5b01205[ACS Full Text], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1SlsLbO&md5=4fe61e4415a08cc9ffc7cb0c0734b541Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman PrimateLi, Junfeng; Zhang, Xiang; Jin, Hongjun; Fan, Jinda; Flores, Hubert; Perlmutter, Joel S.; Tu, ZhudeJournal of Medicinal Chemistry (2015), 58 (21), 8584-8600CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of fluorine-contg. PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10 (I). Twenty of the 22 new analogs had high potency and selectivity for PDE10A (<5 nM). Seven F-18 labeled compds. were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ∼2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a-d [II: R1 = 4-fluoroquinol-2-yl, 4-(fluoromethyl)quinolin-2-yl, 4-(3-fluoropropyl)quinolin-2-yl, and 4-(2-fluoroethoxy)quinolin-2-yl, resp.] and [18F]20a [II: R1 = 3-(2-fluoroethoxy)quinolin-2-yl]. MicroPET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equil. kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington's disease and schizophrenia.328Bajjalieh, S. M.; Peterson, K.; Linial, M.; Scheller, R. H. Brain contains two forms of synaptic vesicle protein 2. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 2150– 2154, DOI: 10.1073/pnas.90.6.2150[Crossref], [PubMed], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXisFWqsrk%253D&md5=6b798d3ff7379b63676c14888f7737f0Brain contains two forms of synaptic vesicle protein 2Bajjalieh, Sandra M.; Peterson, Karen; Linial, Michal; Scheller, Richard H.Proceedings of the National Academy of Sciences of the United States of America (1993), 90 (6), 2150-4CODEN: PNASA6; ISSN:0027-8424.To det. whether synaptic vesicle protein 2 (SV2) is a member of a family of vesicular proteins, the SV2 clone was used to screen for similar cDNAs in rat brain. The authors characterized 42 clones, 25 of which encode SV2 and 4 of which encode a protein, SV2B, that is 65% identical and 78% similar to SV2. The protein encoded by the SV2B cDNA is recognized by the monoclonal antibody that defines the SV2 protein. When SV2B is expressed in COS cells, antibody labeling is reticular in nature, suggesting that SV2B, like SV2 (hence, SV2A), is segregated to intracellular membranes. The expression of SV2B is limited to neural tissue. While both forms of SV2 are expressed in all brain regions, SV2B is expressed at highest levels in the cortex and hippocampus, whereas the highest level of expression of SV2A is in subcortical regions. Therefore, the SV2 proteins, like other characterized synaptic vesicle proteins, comprise a small gene family.329Janz, R.; Südhof, T. C. SV2C is a synaptic vesicle protein with an unusually restricted localization: Anatomy of a synaptic vesicle protein family. Neuroscience 1999, 94, 1279– 1290, DOI: 10.1016/S0306-4522(99)00370-X[Crossref], [PubMed], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXotVGjtbc%253D&md5=5dcd49821be0a2b46658691884f5ffd0SV2C is a synaptic vesicle protein with an unusually restricted localization: anatomy of a synaptic vesicle protein familyJanz, R.; Sudhof, T. C.Neuroscience (Oxford) (1999), 94 (4), 1279-1290CODEN: NRSCDN; ISSN:0306-4522. (Elsevier Science Ltd.)The authors describe here the identification and mol. characterization of a new brain protein that they named SV2C because it is homologous to the synaptic vesicle proteins, SV2A and SV2B, and because it is also recognized by the monoclonal SV2 antibody that led to the initial discovery of SV2A and SV2B. SV2C is more closely related to SV2A (62% identity) than to SV2B (57% identity), and contains 12 transmembrane regions similar to these proteins. To characterize SV2C and compare its properties and localization with those of SV2A and SV2B, the authors raised an SV2C-specific antibody. Using this antibody, the authors show that SV2C is an N-glycosylated protein that is concd. on small synaptic vesicles; in addn., it is found on microvesicles in adrenal chromaffin cells. The authors evaluated the relative localization of the 3 SV2 isoforms by staining rat brain sections with antibodies specific for SV2A, SV2B, and SV2C. Anal. of the resulting staining patterns confirmed previous conclusions that SV2A is ubiquitously expressed in virtually all synapses. SV2B, although more restricted in distribution, was also found in a wide variety of synapses throughout the brain. In striking contrast to this general localization and to similarly wide distributions of other synaptic vesicle proteins, SV2C was obsd. only in few brain areas. High levels of SV2C were found primarily in phylogenetically old brain regions such as the pallidum, the substantia nigra, the midbrain, the brainstem, and the olfactory bulb. SV2C was undetectable in the cerebral cortex and the hippocampus, and found at low levels in the cerebellar cortex. The data suggest that closely related members of a synaptic vesicle protein family can either have very general (SV2A) or restricted distributions (SV2C), possibly in order to allow specialization in the regulation of the expression or of the function of these abundant synaptic vesicle proteins.330Heurling, K.; Ashton, N. J.; Leuzy, A.; Zimmer, E. R.; Blennow, K.; Zetterberg, H.; Eriksson, J.; Lubberink, M.; Schöll, M. Synaptic vesicle protein 2A as a potential biomarker in synaptopathies. Mol. Cell. Neurosci. 2019, 97, 34– 42, DOI: 10.1016/j.mcn.2019.02.001[Crossref], [PubMed], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXks1eisLw%253D&md5=2f4ffa7bf68dbc4a6d93a57956f0f107Synaptic vesicle protein 2A as a potential biomarker in synaptopathiesHeurling, Kerstin; Ashton, Nicholas J.; Leuzy, Antoine; Zimmer, Eduardo R.; Blennow, Kaj; Zetterberg, Henrik; Eriksson, Jonas; Lubberink, Mark; Schoell, MichaelMolecular and Cellular Neuroscience (2019), 97 (), 34-42CODEN: MOCNED; ISSN:1044-7431. (Elsevier B.V.)A review. Measuring synaptic d. in vivo using positron emission tomog. (PET) imaging-based biomarkers targeting the synaptic vesicle protein 2A (SV2A) has received much attention recently due to its potential research and clin. applications in synaptopathies, including neurodegenerative and psychiatric diseases. Fluid-based biomarkers in proteinopathies have previously been suggested to provide information on pathol. and disease status that is complementary to PET-based measures, and the same can be hypothesized with respect to SV2A. This review provides an overview of the current state of SV2A PET imaging as a biomarker of synaptic d., the potential role of fluid-based biomarkers for SV2A, and related future perspectives.331Mendoza-Torreblanca, J. G.; Vanoye-Carlo, A.; Phillips-Farfán, B. V.; Carmona-Aparicio, L.; Gómez-Lira, G. Synaptic vesicle protein 2A: Basic facts and role in synaptic function. Eur. J. Neurosci. 2013, 38, 3529– 3539, DOI: 10.1111/ejn.12360[Crossref], [PubMed], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252FjsFShtg%253D%253D&md5=e0c218b1342f09fb69110d8beb93cfd8Synaptic vesicle protein 2A: basic facts and role in synaptic functionMendoza-Torreblanca Julieta Griselda; Vanoye-Carlo America; Phillips-Farfan Bryan Victor; Carmona-Aparicio Liliana; Gomez-Lira GiselaThe European journal of neuroscience (2013), 38 (11), 3529-39 ISSN:.In recent years, there has been considerable interest in determining the function of synaptic vesicle protein 2A and its role as a target for antiepileptic drugs. Although it is known that synaptic vesicle protein 2A is involved in normal synaptic vesicle function, its participation in synaptic vesicle cycling and neurotransmitter release in normal and pathological conditions is unclear. However, the experimental evidence suggests that synaptic vesicle protein 2A could be a vesicular transporter, regulate synaptic exocytosis as a gel matrix, or modulate synaptotagmin-1 activity. This review describes and discusses the participation of synaptic vesicle protein 2A in synaptic modulation in normal and pathological conditions.332Koole, M.; van Aalst, J.; Devrome, M.; Mertens, N.; Serdons, K.; Lacroix, B.; Mercier, J.; Sciberras, D.; Maguire, P.; Van Laere, K. Quantifying SV2A density and drug occupancy in the human brain using [11C]UCB-J PET imaging and subcortical white matter as reference tissue. Eur. J. Nucl. Med. Mol. Imaging 2019, 46, 396– 406, DOI: 10.1007/s00259-018-4119-8[Crossref], [PubMed], [CAS], Google Scholar332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFCku7bM&md5=865e8f1e0b40ffa9f924be7871a300a0Quantifying SV2A density and drug occupancy in the human brain using [11C]UCB-J PET imaging and subcortical white matter as reference tissueKoole, Michel; van Aalst, June; Devrome, Martijn; Mertens, Nathalie; Serdons, Kim; Lacroix, Brigitte; Mercier, Joel; Sciberras, David; Maguire, Paul; Van Laere, KoenEuropean Journal of Nuclear Medicine and Molecular Imaging (2019), 46 (2), 396-406CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: A [11C]UCB-J blocking study was performed in healthy volunteers to validate simplified, non-invasive measures for quantifying presynaptic SV2A expression using subcortical white matter as ref. tissue. Methods: Ninety minutes dynamic [11C]UCB-J PET scanning with arterial blood sampling was performed in 10 healthy volunteers (8 M/2F; age 27.6 ± 10.0 yrs), before and after administration of a novel chem. entity with selective affinity for SV2A. The centrum semi-ovale (SO) was validated as ref. region by comparing baseline and post treatment distribution vol. (VT). Using SO as ref. tissue, Binding Potential (BPSO) using a Simplified Ref. Tissue Model (SRTM, down to 60 min acquisition) and Standardized Uptake Value Ratios (60-90 min post injection - SUVRSO,60-90min) were compared with regional distribution vol. ratios (DVR). Next, SV2A occupancy values based on SRTM BPSO and SUVRSO,60-90min were compared to occupancy ests. using regional VT values and a Lassen plot. Results: After pretreatment, regional VT values were reduced significantly except for SO. Highly significant correlations were found between DVR, SRTM BPSO and SUVRSO,60-90min. Compared to DVR, baseline SRTM BPSO showed a small bias (≤ 6.1%) with lower precision for shorter acquisition times, while SUVRSO,60-90min showed 3.5% bias with similar precision. Differences between SV2A occupancy values based on SUVRSO,60-90min and occupancy ests. using VT and a Lassen plot were small but significant, while negligible bias was found for SRTM based occupancy ests. (at least 70 min acquisition). Conclusion: This [11C]UCB-J blocking study validated SO as a suitable ref. region for non-invasive quantification of SV2A availability and drug occupancy in the human brain. Accurate quantification can be achieved by using either SUVRSO,60-90min with a 60-90 min PET acquisition or SRTM BPSOwith at least 70 min dynamic PET acquisition.333Holmes, S. E.; Scheinost, D.; Finnema, S. J.; Naganawa, M.; Davis, M. T.; DellaGioia, N.; Nabulsi, N.; Matuskey, D.; Angarita, G. A.; Pietrzak, R. H.; Duman, R. S.; Sanacora, G.; Krystal, J. H.; Carson, R. E.; Esterlis, I. Lower synaptic density is associated with depression severity and network alterations. Nat. Commun. 2019, 10, 1529, DOI: 10.1038/s41467-019-09562-7[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M%252FhvVektQ%253D%253D&md5=d2e910216349cc49de47a600f14aae90Lower synaptic density is associated with depression severity and network alterationsHolmes Sophie E; Finnema Sjoerd J; Davis Margaret T; DellaGioia Nicole; Matuskey David; Angarita Gustavo A; Pietrzak Robert H; Duman Ronald S; Sanacora Gerard; Krystal John H; Esterlis Irina; Scheinost Dustin; Naganawa Mika; Nabulsi Nabeel; Matuskey David; Carson Richard E; Pietrzak Robert H; Krystal John H; Esterlis IrinaNature communications (2019), 10 (1), 1529 ISSN:.Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand [(11)C]UCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.334Finnema, S. J.; Nabulsi, N. B.; Eid, T.; Detyniecki, K.; Lin, S.; Chen, M.-K.; Dhaher, R.; Matuskey, D.; Baum, E.; Holden, D.; Spencer, D. D.; Mercier, J.; Hannestad, J.; Huang, Y.; Carson, R. E. Imaging synaptic density in the living human brain. Sci. Transl. Med. 2016, 8, 348ra96, DOI: 10.1126/scitranslmed.aaf6667335Chen, M.-K.; Mecca, A. P.; Naganawa, M.; Finnema, S. J.; Toyonaga, T.; Lin, S.; Najafzadeh, S.; Ropchan, J.; Lu, Y.; McDonald, J. W.; Michalak, H. R.; Nabulsi, N. B.; Arnsten, A. F. T.; Huang, Y.; Carson, R. E.; van Dyck, C. H. Assessing synaptic density in alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018, 75, 1215– 1224, DOI: 10.1001/jamaneurol.2018.1836[Crossref], [PubMed], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252Fosl2kuw%253D%253D&md5=2909e059f92d8b546f57b1eb7d730a4aAssessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic ImagingChen Ming-Kai; Naganawa Mika; Finnema Sjoerd J; Toyonaga Takuya; Lin Shu-Fei; Najafzadeh Soheila; Ropchan Jim; Lu Yihuan; Nabulsi Nabeel B; Huang Yiyun; Carson Richard E; Mecca Adam P; McDonald Julia W; Michalak Hannah R; Arnsten Amy F T; van Dyck Christopher HJAMA neurology (2018), 75 (10), 1215-1224 ISSN:.Importance: Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density. Objective: To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging. Design, Setting, and Participants: This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as 11C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B (11C-PiB) for β-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation. Main Outcomes and Measures: Outcomes were 11C-UCB-J-specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal. Results: Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] β-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] β-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by 11C-UCB-J-PET BPND (cognitively normal participants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BPND was correlated with a composite episodic memory score in the overall sample (R = 0.56; P = .01). Conclusions and Relevance: To our knowledge, this is the first study to investigate synaptic density in vivo in AD using 11C-UCB-J-PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses.336Bahri, M. A.; Plenevaux, A.; Aerts, J.; Bastin, C.; Becker, G.; Mercier, J.; Valade, A.; Buchanan, T.; Mestdagh, N.; Ledoux, D.; Seret, A.; Luxen, A.; Salmon, E. Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H. Alzheimer's Dementia 2017, 3, 481– 486, DOI: 10.1016/j.trci.2017.08.004[Crossref], [CAS], Google Scholar336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7pvVGmtw%253D%253D&md5=a0513a751289295cb03597c806ea75dcMeasuring brain synaptic vesicle protein 2A with positron emission tomography and [(18)F]UCB-HBahri Mohamed Ali; Plenevaux Alain; Aerts Joel; Bastin Christine; Becker Guillaume; Seret Alain; Luxen Andre; Salmon Eric; Mercier Joel; Valade Anne; Buchanan Tim; Mestdagh Nathalie; Ledoux DidierAlzheimer's & dementia (New York, N. Y.) (2017), 3 (4), 481-486 ISSN:.Introduction: Brain distribution of synaptic vesicle protein 2A was measured with fluorine-18 UCB-H ([(18)F]UCB-H) and positron emission tomography (PET). Methods: Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume. Results: [(18)F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship. Discussion: The cerebral distribution of [(18)F]UCB-H is similar to that recently observed with carbon-11 UCB-J ([(11)C]UCB-J). An accurate [(18)F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging.337Bertoglio, D.; Verhaeghe, J.; Miranda, A.; Kertesz, I.; Cybulska, K.; Korat, Š.; Wyffels, L.; Stroobants, S.; Mrzljak, L.; Dominguez, C.; Liu, L.; Skinbjerg, M.; Munoz-Sanjuan, I.; Staelens, S. Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice. J. Cereb. Blood Flow Metab. 2020, 40, 1351– 1362, DOI: 10.1177/0271678X19864081[Crossref], [PubMed], [CAS], Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsVOku7w%253D&md5=87ec9da23705bc19ca4bd04d60afd811Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in miceBertoglio, Daniele; Verhaeghe, Jeroen; Miranda, Alan; Kertesz, Istvan; Cybulska, Klaudia; Korat, Spela; Wyffels, Leonie; Stroobants, Sigrid; Mrzljak, Ladislav; Dominguez, Celia; Liu, Longbin; Skinbjerg, Mette; Munoz-Sanjuan, Ignacio; Staelens, StevenJournal of Cerebral Blood Flow & Metabolism (2020), 40 (6), 1351-1362CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)This study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examd. kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metab. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT(IDIF) values estd. with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K1(IDIF). A scan duration of 60 min was sufficient for reliable VT(IDIF) and K1(IDIF) estns. In vivo metab. of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic d. in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.338Ribeiro, F. M.; Hamilton, A.; Doria, J. G.; Guimaraes, I. M.; Cregan, S. P.; Ferguson, S. S. Metabotropic glutamate receptor 5 as a potential therapeutic target in Huntington’s disease. Expert Opin. Ther. Targets 2014, 18, 1293– 1304, DOI: 10.1517/14728222.2014.948419[Crossref], [PubMed], [CAS], Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslOhu7nE&md5=2f98555f677157f208cc8a1d1c049ef4Metabotropic glutamate receptor 5 as a potential therapeutic target in Huntington's diseaseRibeiro, Fabiola M.; Hamilton, Alison; Doria, Juliana G.; Guimaraes, Isabella M.; Cregan, Sean P.; Ferguson, Stephen SGExpert Opinion on Therapeutic Targets (2014), 18 (11), 1293-1304CODEN: EOTTAO; ISSN:1472-8222. (Informa Healthcare)Introduction: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein, which underlies the loss of striatal and cortical neurons. Glutamate has been implicated in a no. of neurodegenerative diseases, and several studies suggest that the metabotropic glutamate receptor 5 (mGluR5) may represent a target for the treatment of HD. Areas covered: The main goal of this review is to discuss the current data in the literature regarding the role of mGluR5 in HD and evaluate the potential of mGluR5 as a therapeutic target for the treatment of HD. MGluR5 is highly expressed in the brain regions affected in HD and is involved in movement control. Moreover, mGluR5 interacts with htt and mutated htt profoundly affects mGluR5 signaling. However, mGluR5 stimulation can activate both neuroprotective and neurotoxic signaling pathways, depending on the context of activation. Expert opinion: Although the data published so far strongly indicate that mGluR5 plays a major role in HD-assocd. neurodegeneration, htt aggregation and motor symptoms, it is not clear whether mGluR5 stimulation can diminish or intensify neuronal cell loss and HD progression. Thus, future expts. will be necessary to further investigate the outcome of drugs acting on mGluR5 for the treatment of neurodegenerative diseases.339Bertoglio, D.; Kosten, L.; Verhaeghe, J.; Thomae, D.; Wyffels, L.; Stroobants, S.; Wityak, J.; Dominguez, C.; Mrzljak, L.; Staelens, S. Longitudinal characterization of mGluR5 using 11C-ABP688 PET imaging in the Q175 mouse model of Huntington disease. J. Nucl. Med. 2018, 59, 1722– 1727, DOI: 10.2967/jnumed.118.210658[Crossref], [PubMed], [CAS], Google Scholar339https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXktVajs78%253D&md5=ddaeb6736b0f2c2119a03b738b3d3fd0Longitudinal characterization of mGluR5 using 11C-ABP688 PET imaging in the Q175 mouse model of Huntington diseaseBertoglio, Daniele; Kosten, Lauren; Verhaeghe, Jeroen; Thomae, David; Wyffels, Leonie; Stroobants, Sigrid; Wityak, John; Dominguez, Celia; Mrzljak, Ladislav; Staelens, StevenJournal of Nuclear Medicine (2018), 59 (11), 1722-1728CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Metabotropic glutamate receptor 5 (mGluR5) represents a potential therapeutic target for Huntington disease. Using 11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for mGluR5, we aimed to longitudinally characterize in vivo changes in mGluR5 by means of PET imaging in the Q175 mouse model of Huntington disease. Methods: 11C-ABP688 PET imaging, followed by a CT scan, was performed on 18 heterozygous mice and 18 wild-type (WT) littermates at 3 different time points (6, 9, and 13 mo old). 11C-ABP688 nondisplaceable binding potential (BPND) was calcd. for each time point in striatum and cortex using the cerebellum as the ref. region. In addn., voxel-based statistical parametric mapping (SPM) anal. was performed on BPND images. Postmortem validation of mGluR5 level and neuronal d. was performed on the mice at 6 mo old. Results: The 11C-ABP688 BPND of heterozygous animals was significantly reduced at all time points in the striatum (-13.1%, -13.5%, and -14.2% at 6, 9, and 13 mo, resp.; P < 0.001 for all) and in the cortex (-9.8%, -10.2%, and -10.6%, resp.; P < 0.01 for all), when compared with WT animals. Longitudinal changes in 11C-ABP688 BPND were also found in heterozygous mice, showing a redn. at 13 mo compared with 6 mo (-10.4%, P < 0.05). SPM anal. confirmed reduced BPND in heterozygous compared with WT mice, as well as a time-related decline in 11C-ABP688 binding in the striatum of heterozygous mice. Postmortem anal. confirmed a mGluR5 decrease in both striatum (-36.6%; P < 0.01) and cortex (-16.6%; P < 0.05) in heterozygous mice, whereas no difference in neuronal d. was found. Conclusion: In vivo imaging of mGluR5 using 11C-ABP688 PET/CT revealed a marked redn. in ligand binding in the striatum and cortex of heterozygous mice, compared with WT mice, as well as a temporal decline. This study suggests that 11C-ABP688 PET imaging is a potential biomarker to monitor the progression of, and therapeutic strategies for, Huntington disease.340Fang, X. T.; Eriksson, J.; Antoni, G.; Yngve, U.; Cato, L.; Lannfelt, L.; Sehlin, D.; Syvänen, S. Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [11C]ABP688 PET imaging and ex vivo immunoblotting. Neuropharmacology 2017, 113, 293– 300, DOI: 10.1016/j.neuropharm.2016.10.009[Crossref], [PubMed], [CAS], Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslegsL%252FF&md5=9a6d01f4fb88a58089691d1fcffd0d5bBrain mGluR5 in mice with amyloid beta pathology studied with in vivo [11C]ABP688 PET imaging and ex vivo immunoblottingFang, Xiaotian T.; Eriksson, Jonas; Antoni, Gunnar; Yngve, Ulrika; Cato, Linda; Lannfelt, Lars; Sehlin, Dag; Syvaenen, StinaNeuropharmacology (2017), 113 (Part_A), 293-300CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insol. plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [11C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathol. progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning. In order to convey these neurotoxic effects, Aβo requires interaction with the metabotropic glutamate 5 receptor (mGluR5). The aim was to investigate in vivo mGluR5 changes in an Aβ pathol. model using PET. Wild type C57/BL6 (wt) and AβPP transgenic mice (tg-ArcSwe), 4, 8, and 16 mo old, were PET scanned with [11C]ABP688, which is highly specific to mGluR5, to investigate changes in mGluR5. Mouse brains were extd. postscan and mGluR5 and Aβ protofibril levels were assessed with immunoblotting and ELISA resp. Receptor-dense brain regions (hippocampus, thalamus, and striatum) displayed higher [11C]ABP688 concns. corresponding to mGluR5 expression pattern. Mice had similar uptake levels of [11C]ABP688 regardless of genotype or age. Immunoblotting revealed general decline in mGluR5 expression and elevated levels of mGluR5 in 16 mo old tg-ArcSwe compared with wt mice. [11C]ABP688 could visualize mGluR5 in the mouse brain. In conclusion, mGluR5 levels were found to decrease with age and tended to be higher in tg-ArcSwe compared with wt mice, however these changes could not be quantified with PET.341Ametamey, S. M.; Kessler, L. J.; Honer, M.; Wyss, M. T.; Buck, A.; Hintermann, S.; Auberson, Y. P.; Gasparini, F.; Schubiger, P. A. Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J. Nucl. Med. 2006, 47, 698– 705[PubMed], [CAS], Google Scholar341https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkt1Oisr8%253D&md5=a335f1d6e9bc6c22d20bdf1987ae7bd7Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5Ametamey, Simon M.; Kessler, Lea J.; Honer, Michael; Wyss, Matthias T.; Buck, Alfred; Hintermann, Samuel; Auberson, Yves P.; Gasparini, Fabrizio; Schubiger, Pius A.Journal of Nuclear Medicine (2006), 47 (4), 698-705CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. ABP688 was radiolabeled with 11C by reacting 11C-Me iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime). The affinity of 11C-ABP688 for mGluR5 was detd. by Scatchard anal. using rat whole-brain membranes (without cerebellum). Ex vivo autoradiog., biodistribution, and PET studies with 11C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. The overall synthesis time was 45-50 min from the end of radionuclide prodn. 11C-ABP688 was obtained in good radiochem. yield (35% ± 8%, n = 17, decay cor.), and the specific radioactivity was 150±50 GBq/μmol (n = 17) at the end of the synthesis. Scatchard anal. revealed a single high-affinity binding site with a dissocn. const. of 1.7 ± 0.2 nmol/L and a max. no. of binding sites of 231 ±18 fmol/mg of protein. Ex vivo autoradiog. in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of 11C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of 11C-ABP688 was obsd. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of 11C-ABP688 binding to mGluR5. 11C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.342Akkus, F.; Mihov, Y.; Treyer, V.; Ametamey, S. M.; Johayem, A.; Senn, S.; Rösner, S.; Buck, A.; Hasler, G. Metabotropic glutamate receptor 5 binding in male patients with alcohol use disorder. Transl. Psychiatry 2018, 8, 17, DOI: 10.1038/s41398-017-0066-6[Crossref], [PubMed], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MzptFWlug%253D%253D&md5=e6dc3a4eeac0efbf607c5ceb142f9342Metabotropic glutamate receptor 5 binding in male patients with alcohol use disorderAkkus Funda; Mihov Yoan; Hasler Gregor; Treyer Valerie; Johayem Anass; Buck Alfred; Ametamey Simon M; Senn Smeralda; Rosner SusanneTranslational psychiatry (2018), 8 (1), 17 ISSN:.Glutamate signaling plays a major role in addiction. Preclinical research strongly suggests an implication of G-protein-coupled metabotropic glutamate receptor subtype 5 (mGluR5) in nicotine addiction and alcohol use disorder. In humans, smoking is related to a global reduction in mGluR5 availability. In the present study, we investigated mGluR5 in vivo in patients with alcohol use disorder without the confounding effects of smoking. A total of 14 male subjects with alcohol use disorder and at least a 25-day abstinence and 14 matched male non-smoking healthy controls were included in the study. We employed positron emission tomography (PET) with the mGluR5-specific radiotracer [11C]ABP688, using a bolus/infusion protocol. We found increased mGluR5 DVR in several regions within the temporal lobe in patients, as compared to controls. The largest between-group difference was in the amygdala. There was a marked positive relation between mGluR5 DVR in the anterior cingulate and mGluR5 DVR in the orbitofrontal cortex in patients, but not in controls. In patients, lower temptation to drink was related to higher amygdala mGluR5 DVR. We did not find altered mGluR5 DVR in the basal ganglia of subjects recovering from alcohol use disorder. In conclusion, our study provides clinical evidence for altered mGluR5 signaling in the amygdala in alcohol use disorder. This alteration was associated with the temptation to drink. In addition, this study suggests abnormal mGluR5 signaling in a network underlying reward-related behavioral flexibility. These findings strengthen the case for pharmacological agents acting on mGluR5 as promising candidates for the treatment of alcohol use disorder.343Treyer, V.; Gietl, A. F.; Suliman, H.; Gruber, E.; Meyer, R.; Buchmann, A.; Johayem, A.; Unschuld, P. G.; Nitsch, R. M.; Buck, A.; Ametamey, S. M.; Hock, C. Reduced uptake of [11C]-ABP688, a PET tracer for metabolic glutamate receptor 5 in hippocampus and amygdala in Alzheimer’s dementia. Brain Behav. 2020, 10, e01632 DOI: 10.1002/brb3.1632344Ametamey, S. M.; Treyer, V.; Streffer, J.; Wyss, M. T.; Schmidt, M.; Blagoev, M.; Hintermann, S.; Auberson, Y.; Gasparini, F.; Fischer, U. C.; Buck, A. Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688. J. Nucl. Med. 2007, 48, 247– 252[PubMed], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVKmsb0%253D&md5=be3ec54c117f3789e4482b1e138568b3Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688Ametamey, Simon M.; Treyer, Valerie; Streffer, Johannes; Wyss, Matthias T.; Schmidt, Mark; Blagoev, Milen; Hintermann, Samuel; Auberson, Yves; Gasparini, Fabrizio; Fischer, Uta C.; Buck, AlfredJournal of Nuclear Medicine (2007), 48 (2), 247-252CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime (11C-ABP688), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: Six healthy male volunteers (mean age, 25 y; range, 21-33 y) were studied. Brain perfusion (15O-H2O) was measured immediately before each 11C-ABP688 PET scan. For anat. coregistration, T1-weighted MRI was performed on each subject. Arterial blood samples for the detn. of the arterial input curve were obtained at predefined time points, and 11C-ABP688 uptake was assessed quant. using a 2-tissue-compartment model. Results: An initial rapid uptake of radioactivity followed by a gradual clearance from all examd. brain regions was obsd. Relatively high radioactivity concns. were obsd. in mGluR5-rich brain regions such as the anterior cingulate, medial temporal lobe, amygdala, caudate, and putamen, whereas radioactivity uptake in the cerebellum and white matter, regions known to contain low densities of mGluR5, was low. Specific distribution vol. as an outcome measure of mGluR5 d. in the various brain regions ranged from 5.45 ± 1.47 (anterior cingulate) to 1.91 ± 0.32 (cerebellum), and the rank order of the corresponding specific distribution vols. of 11C-ABP688 in cortical regions was temporal > frontal > occipital > parietal. The metab. of 11C-ABP688 in plasma was rapid; at 60 min after injection, 25% ± 0.03% of radioactivity measured in the plasma of healthy volunteers was intact parent compd. Conclusion: The results of these studies indicate that 11C-ABP688 has suitable characteristics and is a promising PET ligand for imaging mGluR5 distribution in humans. Furthermore, it could be of great value for the selection of appropriate doses of clin. relevant candidate drugs that bind to mGluR5 and for PET studies of patients with psychiatric and neurol. disorders.345Paoletti, P.; Bellone, C.; Zhou, Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 2013, 14, 383– 400, DOI: 10.1038/nrn3504[Crossref], [PubMed], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvVSit7Y%253D&md5=f69790da360242d491bf1a5eb146613dNMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and diseasePaoletti, Pierre; Bellone, Camilla; Zhou, QiangNature Reviews Neuroscience (2013), 14 (6), 383-400CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)A review. NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit compn. of NMDARs is plastic, resulting in a large no. of receptor subtypes. As each receptor subtype has distinct biophys., pharmacol. and signaling properties, there is great interest in detg. whether individual subtypes carry out specific functions in the CNS in both normal and pathol. conditions. Here, we review the effects of subunit compn. on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.346Haider, A.; Herde, A. M.; Krämer, S. D.; Varisco, J.; Keller, C.; Frauenknecht, K.; Auberson, Y. P.; Temme, L.; Robaa, D.; Sippl, W.; Schibli, R.; Wünsch, B.; Mu, L.; Ametamey, S. M. Preclinical evaluation of benzazepine-based PET radioligands (R)- and (S)-11C-Me-NB1 reveals distinct enantiomeric binding patterns and a tightrope walk between GluN2B- and σ1-receptor-targeted PET imaging. J. Nucl. Med. 2019, 60, 1167– 1173, DOI: 10.2967/jnumed.118.221051[Crossref], [PubMed], [CAS], Google Scholar346https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsF2mtA%253D%253D&md5=e32447d3f8fc88a2625b278fc4849001Preclinical evaluation of benzazepine-based PET radioligands (R)- and (S)-11C-Me-NB1 reveals distinct enantiomeric binding patterns and a tightrope Walk Between GluN2B- and σ 1-receptor-targeted PET imagingHaider, Ahmed; Herde, Adrienne Muller; Kramer, Stefanie D.; Varisco, Jasmine; Keller, Claudia; Frauenknecht, Katrin; Auberson, Yves P.; Temme, Louisa; Robaa, Dina; Sippl, Wolfgang; Schibli, Roger; Wunsch, Bernhard; Mu, Linjing; Ametamey, Simon M.Journal of Nuclear Medicine (2019), 60 (8), 1167-1173CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)The study aims to investigate the performance characteristics of the enantiomers of 11C-Me-NB1, a recently reported PET imaging probe that targets the GluN2B subunit of N-methyl-D-aspartate (NMDA) receptors. Ref. compd. Me-NB1 (inhibition const. for hGluN1/GluN2B, 5.4 nM) and the phenolic precursor were prepd. via multistep synthesis. Following chiral resoln. by high-performance liq. chromatog., enantiopure precursor compds., (R)-NB1 and (S)-NB1, were labeled with 11C and validated in rodents using in vitro/ex vivo autoradiog., PET expts., and dose-response studies. To illustrate the translational relevance, (R)-11C-Me-NB1 was validated in autoradiog. studies using postmortem human GluN2B-rich cortical and GluN2B-deficient cerebellar brain slices. To det. target engagement, receptor occupancy was assessed at different plasma concns. of CP101,606, a GluN2B receptor antagonist. The radiosynthesis of (R)- and (S)-11C-Me-NB1 was accomplished in 42% ± 9% (decay-cor.) radiochem. yields. Molar activity ranged from 40 to 336 GBq/μmol, and an excellent radiochem. purity of greater than 99% was achieved. Although (R)-11C-Me-NB1 displayed heterogeneous accumulation with high selectivity for the GluN2B-rich forebrain, (S)-11nt brain, (R)-11C-Me-NB1 showed in postmortem human brain tissues higher binding in the cortex than in the cerebellum. Coincubation of the GluN2B-antagonist CERC-301 (1 μM) reduced cortical but not cerebellar binding, demonstrating the specificity of (R)-11C-Me-NB1 binding to the human GluN2B-contg. NMDA receptor. In vivo specificity of (R)-11CMe-NB1 in the GluN2B-expressing cortex, striatum, thalamus, and hippocampus was demonstrated by PET imaging in rodents. Applying GluN2B-antagonist eliprodil, an evident dose-response behavior was obsd. with (R)-11C-Me-NB1 but not with (S)-11CMe-NB1. Our findings further underline the tightrope walk between GluN2B- and σ1-receptor-targeted imaging, illustrated by the entirely different receptor binding behavior of the 2 radioligand enantiomers. (R)-11C-Me-NB1 is a highly selective and specific PET radioligand for imaging the GluN2B subunit of the NMDA receptor. The entirely different receptor binding behavior of (R)-11C-Me-NB1 and (S)-11C-Me-NB1 raises awareness of a delicate balance that is underlying the selective targeting of either GluN2Bcarrying NMDA or σ1-receptors.347Krämer, S. D.; Betzel, T.; Mu, L.; Haider, A.; Herde, A. M.; Boninsegni, A. K.; Keller, C.; Szermerski, M.; Schibli, R.; Wünsch, B.; Ametamey, S. M. Evaluation of 11 C-Me-NB1 as a potential PET radioligand for measuring GluN2B-containing NMDA receptors, drug occupancy, and receptor cross talk. J. Nucl. Med. 2018, 59, 698– 703, DOI: 10.2967/jnumed.117.200451[Crossref], [PubMed], [CAS], Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlKgtrzJ&md5=7a65e25cb9ca56581cb90d9b9d2d53a9Evaluation of 11C-Me-NB1 as a potential PET radioligand for measuring GluN2B-containing NMDA receptors, drug occupancy, and receptor cross talkKramer, Stefanie D.; Betzel, Thomas; Mu, Linjing; Haider, Ahmed; Herde, Adrienne Muller; Boninsegni, Anna K.; Keller, Claudia; Szermerski, Marina; Schibli, Roger; Wunsch, Bernhard; Ametamey, Simon M.Journal of Nuclear Medicine (2018), 59 (4), 698-703CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Clin. and preclin. research with modulators at the N-methyl-D- aspartate (NMDA) receptor GluN2B N-terminal domain (NTD) aims for the treatment of various neurol. diseases. The interpreta- tion of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of potential drugs. We have developed 11C-Me-NB1 as a PET tracer for imaging GluN1/GluN2B-contg. NMDA receptors and used it to in- vestigate in rats the dose-dependent receptor occupancy of eli- prodil, a GluN2B NTD modulator. 11C-Me-NB1 was synthesized and characterized by in vitro displacement binding ex- periments with rat brain membranes, in vitro autoradiog., and blocking and displacement expts. by PET and PET kinetic modeling. Receptor occupancy by eliprodil was studied by PET with 11C-Me-NB1. 11C-Me-NB1 was synthesized at 290 ± 90 GBq/mmol molar activity, 7.4 ± 1.9 GBq total activity at the end of synthesis (n = 17), and more than 99% radiochem. purity. 11C- Me-NB1 binding in rat brain was blocked in vitro and in vivo by the NTD modulators Ro-25-6981 and eliprodil. Half-maximal receptor occupancy by eliprodil occurred at 1.5 mg/kg. At 1 mg/kg of elipro- dil, a dose with reported neuroprotective effects, more than 99.5% of binding sites were occupied. In vitro, 11C-Me-NB1 binding was independent of the s-1 receptor (Sigma1R), and the Sigma1R ago- nist (+)-pentazocine did not compete for high-affinity binding. In vivo, a 2.5 mg/kg dose of (+)-pentazocine abolished 11C-Me- NB1-specific binding, indicating an indirect effect of Sigma1R on 11C-Me-NB1 binding. 11C-Me-NB1 is suitable for the in vivo imaging of NMDA GluN1/GluN2B receptors and the assess- ment of receptor occupancy by NTD modulators. GluN1/GluN2B NMDA receptors are fully occupied at neuroprotective doses of eliprodil. Furthermore, 11C-Me-NB1 enables imaging of GluN1/GluN2B NMDA receptor cross talk.348Weeks, R. A.; Cunningham, V. J.; Piccini, P.; Waters, S.; Harding, A. E.; Brooks, D. J. 11C-diprenorphine binding in Huntington’s disease: A comparison of region of interest analysis with statistical parametric mapping. J. Cereb. Blood Flow Metab. 1997, 17, 943– 949, DOI: 10.1097/00004647-199709000-00003[Crossref], [PubMed], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmsVagtbk%253D&md5=eb80135e5fc3ef405766c7a219b02ee011C-diprenorphine binding in Huntington's disease: a comparison of region of interest analysis with statistical parametric mappingWeeks, Robert A.; Cunningham, Vincent J.; Piccini, Paola; Waters, Simon; Harding, Anita E.; Brooks, David J.Journal of Cerebral Blood Flow and Metabolism (1997), 17 (9), 943-949CODEN: JCBMDN; ISSN:0271-678X. (Lippincott-Raven)We compare region of interest (ROI) anal. approaches with statistical parametric mapping (SPM) of 11C-diprenorphine positron emission tomog. findings in five patients with Huntington's disease (HD) and nine age-matched controls. The ROI were placed on caudate, putamen, and an occipital ref. area. Ratios of striatal-occipital uptake from averaged static images centered at 60 min showed a mean 20% redn. in caudate (P = 0.034) and 15% redn. in putamen (P = 0.095) receptor binding in the HD patients. Dynamic data from caudate and putamen ROI, together with a plasma tracer input function, were analyzed using spectral anal. to give regional impulse response functions. Regional data at 60 min after impulse showed a mean 29% decrease in caudate (P = 0.006) and 23% decrease in putamen (P = 0.029) opioid binding in the HD cohort. Parametric images of tracer binding also were produced with spectral anal. on a voxel basis. The images of the unit impulse response function at 60 min showed a mean 31% decrease in caudate (P = 0.005) and a 26% decrease in putamen binding (P = 0.011) in HD. The voxel-based parametric images were transformed into std. stereotactic space, and a between-group comparison (patient vs. controls) was performed with SPM. This approach revealed sym. decreases in caudate (peak 40% decrease, z score = 4.38) and putamen opioid binding (peak 24% decrease, z score = 4.686) with addnl. nonhypothesized changes in cingulate prefrontal, and thalamic areas. The significance and precision of changes measured with spectral anal. applied to dynamic data sets were superior to ROI-based ratio anal. on static images. The SPM replicated the striatal redns. in opioid binding in HD and detected addnl. nonpredicted changes. This study suggests that SPM is a valid alternative to conventional ROI anal. approaches for detg. binding changes with positron emission tomog. and may have advantages over region-based analyses in exploratory studies.349Talbot, P. S.; Narendran, R.; Butelman, E. R.; Huang, Y.; Ngo, K.; Slifstein, M.; Martinez, D.; Laruelle, M.; Hwang, D.-R. 11C-GR103545, a radiotracer for imaging kappa-opioid receptors in vivo with PET: Synthesis and evaluation in baboons. J. Nucl. Med. 2005, 46, 484– 494[PubMed], [CAS], Google Scholar349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXivVCgurY%253D&md5=ff4a001a2ea796bb654cc42dce977a2d11C-GR103545, a radiotracer for imaging κ-opioid receptors in vivo with PET: Synthesis and evaluation in baboonsTalbot, Peter S.; Narendran, Raj; Butelman, Eduardo R.; Huang, Yiyun; Ngo, Kim; Slifstein, Mark; Martinez, Diana; Laruelle, Marc; Hwang, Dah-RenJournal of Nuclear Medicine (2005), 46 (3), 484-494CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Brain κ-opioid receptors (ORs) may be involved in several pathol. conditions, such as addiction, psychosis, and seizures. (±)-4-Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a potent and selective κ-OR agonist. The (-)-isomer, GR103545, is the active enantiomer of GR89696. The aim of this study was to characterize the potential of 11C-GR103545 to image κ-OR in vivo with PET. Methods: Brain uptake of 11C-GR103545 was studied in baboons under control conditions and after blockade by naloxone (1 mg/kg i.v.). Uptake of the racemic 11C-GR89696 and of the inactive enantiomer (+)-11C-GR89696 was also evaluated. Regional total distribution vols. were derived using the arterial input function and a 2-tissue-compartment model. Results: 11C-GR103545 showed excellent brain penetration and uptake kinetics, with significant washout obsd. within the time frame of the PET expt. Naloxone pretreatment did not affect cerebellar total distribution vol. and reduced total distribution vol. in other regions to a level comparable to that in the cerebellum. The regional pattern of 11C-GR103545 binding potential was consistent with the distribution of κ-OR in primate brain, with highest levels obsd. in anterior cortical regions (prefrontal cortex and cingulate cortex) and striatum. In most regions, the specific-to-nonspecific equil. partition coeff. (V3'') ranged from 1 to 2, predicting reliable quantification. 11C-GR103545 V3'' values were approx. double the 11C-GR89696 V3'' values, whereas (+)-11C-GR89696 V3'' values were negligible, demonstrating the enantiomeric selectivity of the binding and the advantage of using the pure active enantiomer for PET studies. Conclusion: 11C-GR103545 is a promising PET radiotracer for imaging the κ-OR.350Frost, J. J. PET imaging of the opioid receptor: The early years. Nucl. Med. Biol. 2001, 28, 509– 513, DOI: 10.1016/S0969-8051(01)00221-9[Crossref], [PubMed], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksVGrsbc%253D&md5=b56c97f811687432a765b8b0f05378d9PET imaging of the opioid receptor: the early yearsFrost, J. J.Nuclear Medicine and Biology (2001), 28 (5), 509-513CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)A review with 18 refs. is given on the development of opioid receptor imaging in the human brain by positron tomog. Labeling of opiate receptors started with 3H-naloxone in vivo followed by 3H-diprenorphine and 3H-lofentanil. The 1st PET demonstration in humans used 11C-carfentanil.351Frost, J. J.; Wagner, H. N.; Dannals, R. F.; Ravert, H. T.; Links, J. M.; Wilson, A. A.; Burns, H. D.; Wong, D. F.; McPherson, R. W.; Rosenbaum, A. E.; Kuhar, M. J.; Snyder, S. H. Imaging opiate receptors in the human brain by positron tomography. Journal of Computer Assisted Tomography. 1985, 9, 231– 236, DOI: 10.1097/00004728-198503000-00001[Crossref], [PubMed], [CAS], Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M7jt1Shsw%253D%253D&md5=37046593b372b13385ae5ec953709fbbImaging opiate receptors in the human brain by positron tomographyFrost J J; Wagner H N Jr; Dannals R F; Ravert H T; Links J M; Wilson A A; Burns H D; Wong D F; McPherson R W; Rosenbaum A EJournal of computer assisted tomography (1985), 9 (2), 231-6 ISSN:0363-8715.Carfentanil is a potent, synthetic opiate that binds to mu opiate receptors with very high affinity (KI = 0.051 nM, 37 degrees C). In rat brain, carfentanil is 90 and 250 times more selective for mu opiate receptors compared with delta and kappa opiate receptors, respectively. Carbon-11-carfentanil was synthesized by reacting [11C]methyliodide with the carboxylic acid precursor of carfentanil. Carbon-11-carfentanil was injected intravenously in man and a baboon and the distribution of the radioactivity in the brain was monitored using positron emission tomography. High concentrations of radioactivity were observed in the basal ganglia and thalamus, intermediate concentrations in the frontal and parietal cerebral cortex, and low concentrations in the cerebellum and occipital cortex; this distribution corresponds to the known regional density of opiate receptors measured using in vitro techniques. This heterogeneous distribution could be abolished by pretreatment with naloxone (1 mg/kg), an opiate antagonist. The percent inhibition of binding by naloxone is approximately 90% in the caudate nucleus and medial thalamus for the period 30-60 min after injection; therefore, this method is associated with a high level of specific binding to opiate receptors compared with nonspecific binding sites. The ability to measure opiate receptors in vivo in man makes it possible to study a variety of neurologic and psychiatric disorders in which opiate receptors are thought to be abnormal and to study physiologic role of opiate receptors in the central nervous system.352Zubieta, J.-K.; Gorelick, D. A.; Stauffer, R.; Ravert, H. T.; Dannals, R. F.; Frost, J. J. Increased mu opioid receptor binding detected by PET in cocaine–dependent men is associated with cocaine craving. Nat. Med. 1996, 2, 1225– 1229, DOI: 10.1038/nm1196-1225[Crossref], [PubMed], [CAS], Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xms1WqtLo%253D&md5=4414aa269abf048c4b7ce3bcefd49107Increased mu opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine cravingZubieta, Jon-Kar; Gorelick, David A.; Stauffer, Robin; Ravert, Hayden T.; Dannals, Robert F.; Frost, J. JamesNature Medicine (New York) (1996), 2 (11), 1225-1229CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Co.)The endogenous opioid system has been recently implicated in the reinforcing actions of cocaine and other addictive drugs. In this study we examd. μ opioid receptor binding in ten cocaine-dependent men and seven nonaddicted controls using positron emission tomog. and [11C]carfentanil. Mu opioid binding was increased in several brain regions of the cocaine addicts studied 1-4 days after their last use of cocaine. Binding was pos. correlated with the severity of cocaine craving experienced at the time. The upregulation of μ opioid receptor binding persisted after 4 wk of monitored cocaine abstinence. These findings demonstrate for the first time the involvement of the endogenous opioid system in cocaine dependence and cocaine craving in living human subjects.353Gorelick, D. A.; Kim, Y. K.; Bencherif, B.; Boyd, S. J.; Nelson, R.; Copersino, M.; Endres, C. J.; Dannals, R. F.; Frost, J. J. Imaging brain mu-opioid receptors in abstinent cocaine users: Time course and relation to cocaine craving. Biol. Psychiatry 2005, 57, 1573– 1582, DOI: 10.1016/j.biopsych.2005.02.026[Crossref], [PubMed], [CAS], Google Scholar353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlt1Grsb8%253D&md5=3c0ca2be00051adc4bd89bcc2502183eImaging brain Mu-opioid receptors in abstinent cocaine users: time course and relation to cocaine cravingGorelick, David A.; Kim, Yu Kyeong; Bencherif, Badreddine; Boyd, Susan J.; Nelson, Richard; Copersino, Marc; Endres, Christopher J.; Dannals, Robert F.; Frost, J. JamesBiological Psychiatry (2005), 57 (12), 1573-1582CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)Background: Cocaine treatment upregulates brain mu-opioid receptors (mOR) in animals. Human data regarding this phenomenon are limited. We previously used positron emission tomog. (PET) with [11C]-carfentanil to show increased mOR binding in brain regions of 10 cocaine-dependent men after 1 and 28 days of abstinence. Methods: Regional brain mOR binding potential (BP) was measured with [11C]carfentanil PET scanning in 17 cocaine users over 12 wk of abstinence on a research ward and in 16 healthy control subjects. Results: Mu-opioid receptor BP was increased in the frontal, anterior cingulate, and lateral temporal cortex after 1 day of abstinence. Mu-opioid receptor BP remained elevated in the first two regions after 1 wk and in the anterior cingulate and anterior frontal cortex after 12 wk. Increased binding in some regions at 1 day and 1 wk was pos. correlated with self-reported cocaine craving. Mu-opioid receptor BP was significantly correlated with percentage of days with cocaine use and amt. of cocaine used per day of use during the 2 wk before admission and with urine benzoylecgonine concn. at the first PET scan. Conclusions: These results suggest that chronic cocaine use influences endogenous opioid systems in the human brain and might explain mechanisms of cocaine craving and reinforcement.354Weerts, E. M.; Wand, G. S.; Kuwabara, H.; Munro, C. A.; Dannals, R. F.; Hilton, J.; Frost, J. J.; McCaul, M. E. Positron emission tomography imaging of mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjects: PET imaging of opioid receptors in alcoholics. Alcohol.: Clin. Exp. Res. 2011, 35, 2162– 2173, DOI: 10.1111/j.1530-0277.2011.01565.x[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVCqsL4%253D&md5=2905b03db0df3d05ab7d51304f37bca7Positron emission tomography imaging of Mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjectsWeerts, Elise M.; Wand, Gary S.; Kuwabara, Hiroto; Munro, Cynthia A.; Dannals, Robert F.; Hilton, John; Frost, J. James; McCaul, Mary E.Alcoholism: Clinical & Experimental Research (2011), 35 (12), 2162-2173CODEN: ACRSDM; ISSN:0145-6008. (Wiley-Blackwell)Background: The endogenous opioid system plays a significant role in alc. dependence. The goal of the current study was to investigate regional brain mu-opioid receptor (MOR) and delta-opioid receptor (DOR) availability in recently abstinent alc.-dependent and age-matched healthy control men and women with positron emission tomog. (PET) imaging. Methods: Alc.-dependent subjects completed an inpatient protocol, which included medically supervised withdrawal and PET imaging on day 5 of abstinence. Control subjects completed PET imaging following an overnight stay. PET scans with the MOR-selective ligand [11C]carfentanil (CFN) were completed in 25 alc.-dependent and 30 control subjects. Most of these same subjects (20 alc.-dependent subjects and 18 controls) also completed PET scans with the DOR-selective ligand [11C]methylnaltrindole (MeNTL). Results: Vols. of interest and statistical parametric mapping analyses indicated that alc.-dependent subjects had significantly higher [11C]CFN binding potential (BPND) than healthy controls in multiple brain regions including the ventral striatum when adjusting for age, gender, and smoking status. There was an inverse relationship between [11C]CFN BPND and craving in several brain regions in alc.-dependent subjects. Groups did not differ in [11C]MeNTL BPND; however, [11C]MeNTL BPND in caudate was pos. correlated with recent alc. drinking in alc.-dependent subjects. Conclusions: Our observation of higher [11C]CFN BPND in alc.-dependent subjects can result from up-regulation of MOR and/or redn. in endogenous opioid peptides following long-term alc. consumption, dependence, and/or withdrawal. Alternatively, the higher [11C]CFN BPND in alc.-dependent subjects may be an etiol. difference that predisposed these individuals to alc. dependence or may have developed as a result of increased exposure to childhood adversity, stress, and other environmental factors known to increase MOR. Although the direction of group differences in [11C]MeNTL BPND was similar in many brain regions, differences did not achieve statistical significance, perhaps as a result of our limited sample size. Addnl. research is needed to further clarify these relationships. The finding that alc.-dependent subjects had higher [11C]CFN BPND is consistent with a prominent role of the MOR in alc. dependence.355Banati, R. B.; Newcombe, J.; Gunn, R. N.; Cagnin, A.; Turkheimer, F.; Heppner, F.; Price, G.; Wegner, F.; Giovannoni, G.; Miller, D. H.; Perkin, G. D.; Smith, T.; Hewson, A. K.; Bydder, G.; Kreutzberg, G. W.; Jones, T.; Cuzner, M. L.; Myers, R. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000, 123, 2321– 2337, DOI: 10.1093/brain/123.11.2321[Crossref], [PubMed], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M%252FktFertQ%253D%253D&md5=7afeb2a31af663605d53c0a1a65e6d1fThe peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activityBanati R B; Newcombe J; Gunn R N; Cagnin A; Turkheimer F; Heppner F; Price G; Wegner F; Giovannoni G; Miller D H; Perkin G D; Smith T; Hewson A K; Bydder G; Kreutzberg G W; Jones T; Cuzner M L; Myers RBrain : a journal of neurology (2000), 123 ( Pt 11) (), 2321-37 ISSN:0006-8950.This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.356Lloyd, C. M.; Richardson, M. P.; Brooks, D. J.; Al-Chalabi, A.; Leigh, P. N. Extramotor involvement in ALS: PET studies with the GABAA ligand [11C]flumazenil. Brain 2000, 123, 2289– 2296, DOI: 10.1093/brain/123.11.2289[Crossref], [PubMed], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M%252FktFersQ%253D%253D&md5=7f5a9b6baa8dd9a2f5f9df3bca8b5b4eExtramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenilLloyd C M; Richardson M P; Brooks D J; Al-Chalabi A; Leigh P NBrain : a journal of neurology (2000), 123 ( Pt 11) (), 2289-96 ISSN:0006-8950.We used the benzodiazepine GABA(A) marker [(11)C] flumazenil to study cerebral dysfunction in amyotrophic lateral sclerosis (ALS) with PET. Seventeen non-demented patients with clinically definite or probable ALS were scanned and statistical parametric maps were derived to localize changes in regional flumazenil volumes of distribution (FMZVD), which correlate closely with receptor density (B(max)), and the results were compared with those of 17 controls. The ALS group showed statistically significant decreases in relative FMZVD in the prefrontal cortex (areas 9 and 10 bilaterally), parietal cortex (area 7 bilaterally), visual association cortex (area 18 bilaterally) and left motor/premotor cortex (including area 4) (P < 0.001). Relative reductions in FMZVD were also seen in the left ventrolateral and dorsolateral prefrontal cortex (areas 45, 46 and 47), Broca's area and the right temporal (area 21) and right visual association cortex (area 19). These observations suggest that cerebral dysfunction in ALS involves motor/premotor and extramotor areas, particularly the prefrontal regions.357Künig, G.; Leenders, K. L.; Sanchez-Pernaute, R.; Antonini, A.; Vontobel, P.; Verhagen, A.; Günther, I. Benzodiazepine receptor binding in Huntington’s disease: [11C]flumazenil uptake measured using positron emission tomography. Ann. Neurol. 2000, 47, 644– 648, DOI: 10.1002/1531-8249(200005)47:5<644::AID-ANA13>3.0.CO;2-C358Lingford-Hughes, A. R.; Wilson, S. J.; Cunningham, V. J.; Feeney, A.; Stevenson, B.; Brooks, D. J.; Nutt, D. J. GABA-benzodiazepine receptor function in alcohol dependence: A combined 11C-flumazenil PET and pharmacodynamic study. Psychopharmacology (Berl). 2005, 180, 595– 606, DOI: 10.1007/s00213-005-2271-x[Crossref], [PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVSqt7vN&md5=da8b7335e00f7cc7fb5239a686c48da1GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic studyLingford-Hughes, A. R.; Wilson, S. J.; Cunningham, V. J.; Feeney, A.; Stevenson, B.; Brooks, D. J.; Nutt, D. J.Psychopharmacology (Berlin, Germany) (2005), 180 (4), 595-606CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alc. dependence. We used positron emission tomog. (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to det. in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Abstinent male alc. dependent subjects underwent [11C]flumazenil PET to measure occupancy of BDZ receptors by midazolam while recording its pharmacodynamic effects on behavioral and physiol. measures. Rate consts. describing the exchange of [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. A 50% redn. in electroencephalog. (EEG)-measured sleep time was seen in the alc. dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG beta1 power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metab. were found between the groups. In summary, our study suggests that alc. dependence in man is assocd. with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alc. dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.359Myers, J. F.; Comley, R. A.; Gunn, R. N. Quantification of [11C]Ro15–4513 GABAAα5 specific binding and regional selectivity in humans. J. Cereb. Blood Flow Metab. 2017, 37, 2137– 2148, DOI: 10.1177/0271678X16661339[Crossref], [PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFKms74%253D&md5=a1a64d8e83b197a002bbf2f294244034Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humansMyers, Jim FM; Comley, Robert A.; Gunn, Roger N.Journal of Cerebral Blood Flow & Metabolism (2017), 37 (6), 2137-2148CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)[11C]Ro15-4513 has been introduced as a positron emission tomog. radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different anal. approaches has yet to be performed. Using human heterologous competition data, with [11C]Ro15-4513 and the highly selective GABAAα5 selective neg. allosteric modulator Basmisanil (RG1662), we quantify the GABAAα5 selectivity of [11C]Ro15-4513, assess the validity of ref. tissues and evaluate the performance of four different kinetic anal. methods. The results show that [11C]Ro15-4513 has high but not complete selectivity for GABAAα5, with α5 representing around 60-70% of the specific binding in α5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of α5 signal and might be used as ref. regions under certain conditions. Off-target non-selective binding to other GABAA subtypes means that the choice of anal. method and the interpretation of outcome measures must be considered carefully. We discuss the merits of two tissue compartmental model analyses to derive both VT and VS, band-pass spectral anal. for estn. of Vα5 and the simplified ref. tissue model for estn. of BPND.360Diksic, M.; Tohyama, Y.; Takada, A. Brain net unidirectional uptake of alpha-[14C]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp. Neurochem. Res. 2000, 25, 1537– 1546, DOI: 10.1023/A:1026654116999[Crossref], [PubMed], [CAS], Google Scholar360https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovFyhtrs%253D&md5=f170a9fc6e5df59e7b7e78a06f4165b4Brain net unidirectional uptake of α-[14C]methyl-L-tryptophan (α-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and α-MTrpDiksic, Mirko; Tohyama, Yoshihiro; Takada, AkiraNeurochemical Research (2000), 25 (12), 1537-1546CODEN: NEREDZ; ISSN:0364-3190. (Kluwer Academic/Plenum Publishers)The uptake and trapping consts. for labeled tryptophan (Trp) via the serotonin (5-hydroxytryptamine; 5-HT) metabolic pathway and for the incorporation of Trp into proteins, and α-[14C]methyl-L-tryptophan (α-MTrp) were measured. Measurements were done in rats treated with either saline or probenecid (200 mg/kg). In addn., the blood-brain barrier (BBB) permeability surface area products for Trp (PST) and α-MTrp (PSα) were measured in normal rats. The results suggest that, in both groups of rats, there is a highly significant correlation (Pearson Product Moment Correlation (PPMC)) between the brain uptake and trapping consts. for α-MTrp and those of Trp via the 5-HT metabolic pathway, but there is no significant correlation (PPMC) between either of these consts. and the PS products of either compd. There is also no significant correlation (PPMC) between the const. for the Trp incorporation into proteins with any of the other parameters. For all parameters, except Trp incorporation into proteins (α-MTrp is not incorporated into proteins), there was a highly significant correlation between the quantities measured for Trp and α-MTrp. The data presented here strongly suggests that the brain uptake and trapping of α-MTrp relates to brain 5-HT synthesis, and does not relate to the BBB transport or protein incorporation of Trp. On the basis of these results, as well as those previously reported, the authors concluded that trapping (unidirectional uptake) of α-MTrp can be converted to the 5-HT synthesis rates in the brain. From this also follows that labeled α-MTrp is a good tracer for in vivo evaluation of the brain 5-HT synthesis.361Chugani, H. T.; Juhász, C.; Chugani, D. C.; Lawrenson, L.; Muzik, O.; Chakraborty, P. K.; Sood, S. Increased striatal serotonin synthesis following cortical resection in children with intractable epilepsy. Epilepsy Res. 2008, 78, 124– 130, DOI: 10.1016/j.eplepsyres.2007.10.012[Crossref], [PubMed], [CAS], Google Scholar361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVOrsL8%253D&md5=11536dce2403efb889af4f3ffd21f939Increased striatal serotonin synthesis following cortical resection in children with intractable epilepsyChugani, Harry T.; Juhasz, Csaba; Chugani, Diane C.; Lawrenson, Lesley; Muzik, Otto; Chakraborty, Pulak K.; Sood, SandeepEpilepsy Research (2008), 78 (2-3), 124-130CODEN: EPIRE8; ISSN:0920-1211. (Elsevier Ltd.)Summary: Background and purpose: Serotonin is a major regulator of structural brain plasticity, which may occur following cortical resection in humans. In this study we used positron emission tomog. (PET) with alpha[11C]methyl--tryptophan (AMT) to evaluate serotonergic alterations in subcortical structures following cortical resection in children with intractable epilepsy. Methods: AMT uptake in the thalamus and lentiform nucleus was evaluated postoperatively (1-89 mo following resection) in 19 children (mean age: 8.7 years) with a previous cortical resection due to intractable epilepsy. Ten children with partial epilepsy but without resection and seven normal children served as controls. Results: There was an increased AMT uptake in the lentiform nucleus ipsilateral to the resection as compared to the contralateral side (mean asymmetry: 4.2 ± 3.0%), and the asymmetries were significantly higher than those measured in the control groups (p ≤ 0.001). Post-resection asymmetry indexes in the lentiform nucleus correlated inversely with postoperative time (r = -0.67; p = 0.002), but not with age (p = 0.29) or the extent of resection (p = 0.77). In contrast, thalamic AMT uptake asymmetries were not different among the three groups (p = 0.63). Conclusions: Cortical resection results in a sustained increase of AMT uptake in the lentiform nucleus, suggesting increased serotonin synthesis. Serotonergic activation in the deafferented striatum may play a role in the functional reorganization of cortico-striatal projections in humans.362Barnes, N. M.; Sharp, T. A review of central 5-HT receptors and their function. Neuropharmacology 1999, 38, 1083– 1152, DOI: 10.1016/S0028-3908(99)00010-6[Crossref], [PubMed], [CAS], Google Scholar362https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXltVCgsrg%253D&md5=7e92e3b6586ce16c00a1afab5ae06e01A review of central 5-HT receptors and their functionBarnes, Nicholas M.; Sharp, TrevorNeuropharmacology (1999), 38 (8), 1083-1152CODEN: NEPHBW; ISSN:0028-3908. (Elsevier Science Ltd.)A review with ∼700 refs. It is now nearly 5 yr since the last of the currently recognized 5-HT receptors was identified in terms of its cDNA sequence. Over this period, much effort has been directed towards understanding the function attributable to individual 5-HT receptors in the brain. This has been helped, in part, by the synthesis of a no. of compds. that selectively interact with individual 5-HT receptor subtypes-although some 5-HT receptors still lack any selective ligands (e.g., 5-ht1E, 5-ht5A and 5-ht5B receptors). The present review provides background information for each 5-HT receptor subtype and subsequently reviews in more detail the functional responses attributed to each receptor in the brain. Clearly this latter area has moved forward in recent years and this progression is likely to continue given the level of interest assocd. with the actions of 5-HT. This interest is stimulated by the belief that pharmacol. manipulation of the central 5-HT system will have therapeutic potential. In support of which, a no. of 5-HT receptor ligands are currently utilized, or are in clin. development, to reduce the symptoms of CNS dysfunction.363Herholz, K.; Heiss, W. Positron emission tomography in clinical neurology. Molecular Imaging & Biology. 2004, 6, 239– 269, DOI: 10.1016/j.mibio.2004.05.002[Crossref], [PubMed], [CAS], Google Scholar363https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2czmtVGisQ%253D%253D&md5=5d401521383f20decb95714a6b94437ePositron emission tomography in clinical neurologyHerholz Karl; Heiss W-DMolecular imaging and biology (2004), 6 (4), 239-69 ISSN:1536-1632.Positron emission tomography (PET) imaging in clinical neurology serves several purposes: differential diagnosis, especially in the early stage of neurologic disorders, description of pathophysiologic changes that are responsible for manifestation and course of a disease, and evaluation and follow-up of treatment effects. Many of these applications are possible with the most widely available PET tracer, 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Additional tracers are used clinically to detect the disturbance of specific neurotransmitter and receptor systems, blood flow, oxygen metabolism, and amino acid uptake. Main diagnostic issues addressed in this review are early diagnosis of Alzheimer's disease and other dementias, differential diagnosis of movement disorders, diagnosis of recurrent brain tumors, identification of viable tissue in ischemic stroke, and localization of epileptogenic foci. Techniques for presurgical localization of eloquent cortex and monitoring of therapy are presented.364Azmitia, E.; Gannon, P.; Kheck, N.; Whitakerazinitia, P. Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology 1996, 14, 35– 46, DOI: 10.1016/S0893-133X(96)80057-1[Crossref], [PubMed], [CAS], Google Scholar364https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XpvVeqtA%253D%253D&md5=f9c0a5b470a9b8a589a4c243e11cb2a7Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cellsAzmitia, Efrain C.; Gannon, Patrick J.; Kheck, Nancy M.; Whitaker-Azmitia, Patricia M.Neuropsychopharmacology (1996), 14 (1), 35-46CODEN: NEROEW; ISSN:0893-133X. (Elsevier)Activation of 5HT1A receptors produces many different physiol. responses, which may be due to their localization on diverse cells in the brain. A 5-HT1A receptor antipeptide (aa170-186) antibody was produced that showed both high titer for peptide binding and immunocytochem. staining. Studies performed in perfusion-fixed brain tissue showed immunoreactive neurons, glial, and ependymal cells in the rat, mouse, cat, and monkey. Results from the studies of Macaca fascicularis brains are presented. The authors obsd. two main neuronal labeling patterns in the primate brain: (1) A general, diffuse somatodendritic distribution of 5-HT1A receptor immunoreactivity is seen in the raphe nuclei where the dendritic shaft, its branches and spines, and the entire perikaryon are immunolabeled. This pattern is also obsd. in the nucleus locus ceruleus, in scattered large brainstem reticular neurons, and in dentate gyrus hilar interneurons. (2) A discrete localization of 5-HT1A receptor immunoreactivity on the initial axon segment (axon hillock) is noted in pyramidal neurons of layer III and V of cerebral cortex, Cornu Ammonus (1-4) of the hippocampus, and in most brainstem and cervical spinal cord motoneurons. In addn. to neuronal labeling, 5-HT1A receptor immunoreactivity is seen in the cell body and processes of astrocytes, and other nonneuronal cells. This pattern is particularly evident in the white matter of cerebral cortex and spinal cord, the pontine nuclei, the brainstem tectum, and the hilus of the dentate gyrus. The clin. implications of 5-HT1A cellular localization are briefly discussed.365Turner, M. R. [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. Brain 2005, 128, 896– 905, DOI: 10.1093/brain/awh428[Crossref], [PubMed], [CAS], Google Scholar365https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M7lsV2jsg%253D%253D&md5=7ed9b261f178a93c945a21cd82b8051611C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALSTurner M R; Rabiner E A; Hammers A; Al-Chalabi A; Grasby P M; Shaw C E; Brooks D J; Leigh P NBrain : a journal of neurology (2005), 128 (Pt 4), 896-905 ISSN:.The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.366Lanctôt, K. L.; Herrmann, N.; Ganjavi, H.; Black, S. E.; Rusjan, P. M.; Houle, S.; Wilson, A. A. Serotonin-1A receptors in frontotemporal dementia compared with controls. Psychiatry Res., Neuroimaging 2007, 156, 247– 250, DOI: 10.1016/j.pscychresns.2007.07.003[Crossref], [CAS], Google Scholar366https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlGgs7bJ&md5=3bc8bc1ce2c26de6fcbb0c471e5da82cSerotonin-1A receptors in frontotemporal dementia compared with controlsLanctot, Krista L.; Herrmann, Nathan; Ganjavi, Hooman; Black, Sandra E.; Rusjan, Pablo M.; Houle, Sylvain; Wilson, Alan A.Psychiatry Research, Neuroimaging (2007), 156 (3), 247-250CODEN: PSREEK; ISSN:0925-4927. (Elsevier Ltd.)Using PET neuroimaging, we demonstrated that four frontotemporal lobar dementia (FTLD) patients had significantly decreased serotonin 5-HT1A binding potential (BP) compared with controls in all 10 brain regions examd. These pilot data suggest that profound 5-HT1A BP losses may be present and contribute to symptomatol. and treatment response in FTLD.367Goffin, K.; Dedeurwaerdere, S.; Van Laere, K.; Van Paesschen, W. Neuronuclear assessment of patients with epilepsy. Semin. Nucl. Med. 2008, 38, 227– 239, DOI: 10.1053/j.semnuclmed.2008.02.004[Crossref], [PubMed], [CAS], Google Scholar367https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1czltVyntg%253D%253D&md5=f16ac2f3febec0a6dca57282df1475e8Neuronuclear assessment of patients with epilepsyGoffin Karolien; Dedeurwaerdere Stefanie; Van Laere Koen; Van Paesschen WimSeminars in nuclear medicine (2008), 38 (4), 227-39 ISSN:0001-2998.Epilepsy is a common chronic neurological disorder that is controlled with medication in approximately 70% of cases. When partial seizures are recurrent despite the use of antiepileptic drugs, resection of the epileptogenic cortex may be considered. Nuclear medicine plays an important role in the presurgical assessment of patients with refractory epilepsy. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques are used to determine the seizure onset zone, which needs to be resected to render a patient seizure free. Correct localization of the ictal onset zone with the use of SPECT or PET is associated with a better surgical outcome. Ictal perfusion SPECT imaging with (99m)Tc-ethyl cysteinate dimer (ECD) or (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) enables one to detect the seizure onset zone in a majority of cases, especially in patients with temporal lobe epilepsy. Interictal SPECT imaging, which is more widely available, is unreliable to determine the ictal onset zone and is usually only used for comparison with ictal SPECT images. Assessment of the ictal onset zone using subtracted ictal and interictal studies, overlayed on structural imaging has proven to be more sensitive and more specific compared with visual assessment. Video-electroencephalography monitoring in combination with ictal SPECT imaging, however, is only available in specialized centers. It is important to inject the perfusion tracer as early as possible after the beginning of a seizure and to be aware of patterns of seizure propagation. Interictal (18)F-fluorodeoxyglucose (FDG)-PET is routinely used to detect brain areas of hypometabolism, which usually encompass, but tend to be larger than, the seizure onset zone. Also, for assessment of FDG-PET, it is advisable to use an automated technique comparing the patient's images to a normal database in addition to visual interpretation of the images, since automated techniques have proven to be more accurate. In view of the thickness of the cortical ribbon, which may be below the resolution of the PET camera, posthoc partial volume correction or PET reconstruction incorporating the anatomical information of magnetic resonance imaging (MRI), may be useful for optimal assessment of glucose metabolism. Perfusion SPECT and interictal FDG-PET are able to demonstrate areas of abnormal perfusion and metabolism at a distance from the ictal onset zone, which may be associated with cognitive and psychiatric comorbidities, and may represent the functional deficit zone in epilepsy. Part of the functional deficit zone is a dynamic seizure-related process, which may resolve with cessation of seizures. In recent years, novel PET tracers have been developed to visualize not only glucose metabolism but also a wide variety of specific receptor systems. In patients with epilepsy, changes in the gamma-amino-butyric acid(A) receptor, opioid receptor, 5-HT(1A) serotonin receptor, nicotinic acetylcholine receptor systems, and others have been described. Because these tracers are not widely available and the superiority of studying these receptor systems over glucose metabolism in the presurgical evaluation of patients with refractory epilepsy remains to be proven, their use in clinical practice is limited at the moment. Finally, advances in small animal PET scanning allow the in vivo study of the process of epileptogenesis, starting from an initial brain insult to the development of seizures, in animal models of epilepsy. Potential new therapeutic targets may be discovered using this translational approach.368Passchier, J.; van Waarde, A. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. Eur. J. Nucl. Med. 2001, 28, 113– 129, DOI: 10.1007/s002590000394[Crossref], [PubMed], [CAS], Google Scholar368https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovFyjt7g%253D&md5=3964aa4056633399d6ac2843fafaceb1Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous systemPasschier, Jan; van Waarde, ArenEuropean Journal of Nuclear Medicine (2001), 28 (1), 113-129CODEN: EJNMD9; ISSN:0340-6997. (Springer-Verlag)A review with 131 refs. The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behavior, motion sickness and eating disorders, they are an important target for drug therapy. Here, the authors review the radioligands which are available for visualization and quantification of this important neuroreceptor in the human brain, using positron emission tomog. (PET) or single-photon emission tomog. (SPET). More than 20 compds. have been labeled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogs of the agonist, 8-OH-DPAT, structural analogs of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-11C] WAY-100635 (WAY), [carbonyl-11C]desmethyl-WAY-100635 (DWAY),p-[18F]MPPF and [11C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT1A receptor distribution in the brain (even the raphe nuclei are visualized), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centers within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) prodn. of a radioiodinated or technetium-labeled ligand for SPET.369Pike, V. W. Radioligands for PET studies of central 5-HT receptors and re-uptake sites — Current status. Nucl. Med. Biol. 1995, 22, 1011– 1018, DOI: 10.1016/0969-8051(95)02024-1[Crossref], [PubMed], [CAS], Google Scholar369https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XlvFCjtQ%253D%253D&md5=0a8aa8601f9b597465cec1997a0aefb8Radioligands for PET studies of central 5-HT receptors and re-uptake sites - current statusPike, Victor W.Nuclear Medicine and Biology (1995), 22 (8, New Radio-Tracers and Methods of Quality Assurance for Nuclear Medicine Applications), 1011-18CODEN: NMBIEO; ISSN:0883-2897. (Elsevier)A review and discussion, with several refs.370Innis, R. B.; Cunningham, V. J.; Delforge, J.; Fujita, M.; Gjedde, A.; Gunn, R. N.; Holden, J.; Houle, S.; Huang, S.-C.; Ichise, M.; Iida, H.; Ito, H.; Kimura, Y.; Koeppe, R. A.; Knudsen, G. M.; Knuuti, J.; Lammertsma, A. A.; Laruelle, M.; Logan, J.; Maguire, R. P.; Mintun, M. A.; Morris, E. D.; Parsey, R.; Price, J. C.; Slifstein, M.; Sossi, V.; Suhara, T.; Votaw, J. R.; Wong, D. F.; Carson, R. E. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J. Cereb. Blood Flow Metab. 2007, 27, 1533– 1539, DOI: 10.1038/sj.jcbfm.9600493[Crossref], [PubMed], [CAS], Google Scholar370https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXptlSqtrc%253D&md5=77f7e875203e18e1a15d3e2d7fcd4ac6Consensus nomenclature for in vivo imaging of reversibly binding radioligandsInnis, Robert B.; Cunningham, Vincent J.; Delforge, Jacques; Fujita, Masahiro; Gjedde, Albert; Gunn, Roger N.; Holden, James; Houle, Sylvain; Huang, Sung-Cheng; Ichise, Masanori; Iida, Hidehiro; Ito, Hiroshi; Kimura, Yuichi; Koeppe, Robert A.; Knudsen, Gitte M.; Knuuti, Juhani; Lammertsma, Adriaan A.; Laruelle, Marc; Logan, Jean; Maguire, Ralph Paul; Mintun, Mark A.; Morris, Evan D.; Parsey, Ramin; Price, Julie C.; Slifstein, Mark; Sossi, Vesna; Suhara, Tetsuya; Votaw, John R.; Wong, Dean F.; Carson, Richard E.Journal of Cerebral Blood Flow & Metabolism (2007), 27 (9), 1533-1539CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)A review. An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo mol. imaging of reversibly binding radioligands.371Bhagwagar, Z.; Hinz, R.; Taylor, M.; Fancy, S.; Cowen, P.; Grasby, P. Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: A positron emission study with [(11)C]MDL 100,907. Am. J. Psychiatry 2006, 163, 1580– 1587, DOI: 10.1176/ajp.2006.163.9.1580[Crossref], [PubMed], [CAS], Google Scholar371https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28ritFGmtg%253D%253D&md5=5dd5c3caf0260a447a8b0e97b9f656c7Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907Bhagwagar Zubin; Hinz Rainer; Taylor Matthew; Fancy Sabrina; Cowen Philip; Grasby PaulThe American journal of psychiatry (2006), 163 (9), 1580-7 ISSN:0002-953X.OBJECTIVE: A previous positron emission tomography (PET) study reported increased serotonin 5-HT(2A) receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT(2A) receptor ligand [(11)C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT(2A) receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. METHOD: Cortical 5-HT(2A) receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [(11)C]MDL 100,907 in brain tissue. RESULTS: Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT(2A) receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT(2A) receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients. CONCLUSIONS: These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT(2A) receptors. The correlation of increased 5-HT(2A) receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT(2A) receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.372Azmitia, E. C.; Nixon, R. Dystrophic serotonergic axons in neurodegenerative diseases. Brain Res. 2008, 1217, 185– 194, DOI: 10.1016/j.brainres.2008.03.060[Crossref], [PubMed], [CAS], Google Scholar372https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsFCqsLg%253D&md5=73028faf2e2dcb972b9fa7973a4321adDystrophic serotonergic axons in neurodegenerative diseasesAzmitia, Efrain C.; Nixon, RalphBrain Research (2008), 1217 (), 185-194CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)Neurodegenerative diseases such as Parkinson's disease (PD), frontal lobe dementia (FLD) and diffuse Lewy-body dementia (DLBD) have diverse neuropathol. features. Here we report that serotonin fibers are dystrophic in the brains of individuals with these three diseases. In neuropathol. normal (control) brains (n = 3), serotonin axons immunoreactive (IR) with antibodies against the serotonin transporter (5-HTT) protein were widely distributed in cortex (entorhinal and dorsolateral prefrontal), hippocampus and rostral brainstem. 5-HTT-IR fibers-of-passage appeared thick, smooth, and unbranched in medial forebrain bundle, medial lemniscus and cortex white matter. The terminal branches were fine, highly branched and varicose in substantia nigra, hippocampus and cortical gray matter. In the diseased brains, however, 5-HTT-IR fibers in the forebrain were reduced in no. and were frequently bulbous, splayed, tightly clustered and enlarged. Morphometric anal. revealed significant differences in the size distribution of the 5-HTT-IR profiles in dorsolateral prefrontal area between neurodegenerative diseases and controls. Our observations provide direct morphol. evidence for degeneration of human serotonergic axons in the brains of patients with neurodegenerative diseases despite the limited size (n = 3 slices for each region (3) from each brain (4), total slices was n = 36) and the lack of extensive clin. characterization of the analyzed cohort. This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue.373Buck, A.; Gucker, P. M.; Schönbächler, R. D.; Arigoni, M.; Kneifel, S.; Vollenweider, X. F.; Ametamey, S. M.; Burger, C. Evaluation of serotonergic transporters using PET and [11C](+)McN-5652: Assessment of methods. J. Cereb. Blood Flow Metab. 2000, 20, 253– 262, DOI: 10.1097/00004647-200002000-00005[Crossref], [PubMed], [CAS], Google Scholar373https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhs1alur4%253D&md5=4e5a169f39551e093fec756b2117196cEvaluation of serotonergic transporters using PET and [11C](+)McN-5652: assessment of methodsBuck, Alfred; Gucker, Pascale M.; Schonbachler, Roland D.; Arigoni, Michele; Kneifel, Stefan; Vollenweider, Franz X.; Ametamey, Simon M.; Burger, CyrillJournal of Cerebral Blood Flow and Metabolism (2000), 20 (2), 253-262CODEN: JCBMDN; ISSN:0271-678X. (Lippincott Williams & Wilkins)[11C](+)McN-5652 is an established positron emission tomog. tracer used to assess serotonergic transporter d. Several methods have been used to analyze [11C](+)McN-5652 data; however, no evaluation of candidate methods has been published in detail yet. In this study, compartmental modeling using a one-tissue compartment model (K1, k2"), a two-tissue compartment model (K1 to k4), and a noncompartmental method that relies on a ref. region devoid of specific binding sites were assessed. Because of its low d. of serotonergic transporters, white matter was chosen as ref. Parameters related to transporter d. were the total distribution vol. DV" (= K1/k2", one tissue compartment), DVtot (= K1/k1' (1 + k3/k4), two tissue compartments), and Rv (= k3'/k4, noncompartmental method). The DV", DVtot, and Rv values extended over a similar range and reflected the known pattern of serotonergic transporters. However, all parameters related to transporter d. were markedly confounded by nonspecific binding. With regard to K1, the one-tissue compartment model yielded markedly lower values, which were, however, more stable. The minimal study duration needed to det. stable values for the distribution vol. was ∼60 min. The choice of the method to analyze [11C](+)McN-5652 data depends on the situation. Parametric maps of Rv are useful if no information on K1 is needed. If compartmental modeling is chosen, both the one- and the two-tissue compartment models have advantages. The one-tissue compartment model underestimates K1 but yields more robust values. The distribution vols. calcd. with both models contain a similar amt. of information. None of the parameters reflected serotonergic transporter d. in a true quant. manner, as all were confounded by nonspecific binding.374Ginovart, N.; Wilson, A. A.; Meyer, J. H.; Hussey, D.; Houle, S. [11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in cats. Synapse 2003, 47, 123– 133, DOI: 10.1002/syn.10155[Crossref], [PubMed], [CAS], Google Scholar374https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlt1Chsg%253D%253D&md5=70f97154518c6478158709eccfb70fcf[11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in catsGinovart, Nathalie; Wilson, Alan A.; Meyer, Jeffrey H.; Hussey, Doug; Houle, SylvainSynapse (New York, NY, United States) (2003), 47 (2), 123-133CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)The in vivo pharmacol. profile of [11C]-DASB, a new radioligand developed for in vivo imaging of the serotonin transporter (SERT), was evaluated in the cat brain using positron emission tomog. (PET). The in vivo distribution of [11C]-DASB binding was consistent with the known distribution of SERT sites in the cat brain in vitro with high uptakes of radioactivity in the midbrain and thalamus, intermediate levels in striatum, and modest to low levels of radioactivity in the neocortex and cerebellum, resp. [11C]-DASB binding potential (BP) values ranged from about 0.2 in the neocortex to 2.2 in the midbrain. Radioligand binding in all brain regions except cerebellum was markedly reduced following pretreatment with fluoxetine and citalopram, but was unaffected by pretreatment with GBR12909, maprotiline, and haloperidol, indicating specificity of [11C]-DASB binding to the SERT. Two cats were each examd. using PET and [11C]-DASB in a longitudinal fashion (from 30 min and up to 24 days) following a single i.v. dose of: 1. fluoxetine, and 2. citalopram at different dosages. Both drugs induced similar degrees of SERT occupancy at 30 min postinjection (∼90%). A comparison of citalopram and fluoxetine pharmacokinetics in the same animal and at the same dosage (1 mg/kg) showed that citalopram SERT occupancy and plasma half-lives were 9 times and 14 times shorter, resp., than those of fluoxetine and norfluoxetine. In addn., studies performed after injection of the monoamine oxidase inhibitor tranylcypromine suggested that high levels of synaptic serotonin may compete with [11C]-DASB for binding on the SERT. These studies indicate that [11C]-DASB is a suitable PET radioligand for measuring drug occupancy of the SERT in vivo and has potential for monitoring in vivo changes in serotonin levels.375Heiss, W.-D.; Herholz, K. Brain receptor imaging. J. Nucl. Med. 2006, 47, 302– 312[PubMed], [CAS], Google Scholar375https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhslantrk%253D&md5=ddbd0dfb76010abc6f8122f440a59e9aBrain receptor imagingHeiss, Wolf-Dieter; Herholz, KarlJournal of Nuclear Medicine (2006), 47 (2), 302-312CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review. Receptors have a prominent role in brain function, as they are the effector sites of neurotransmission at the postsynaptic membrane, have a regulatory role on presynaptic sites for transmitter reuptake and feedback, and are modulating various functions on the cell membrane. Distribution, d., and activity of receptors in the brain can be visualized by radioligands labeled for SPECT and PET, and the receptor binding can be quantified by appropriate tracer kinetic models, which can be modified and simplified for particular application. Selective radioligands are available for the various transmitter systems, by which the distribution of these receptors in the normal brain and changes in receptor binding during various physiol. activities or resulting from pathol. conditions can be visualized. The quant. imaging for several receptors has gained clin. importance-for example, dopamine (D2) receptors for differential diagnosis of movement disorders and for assessment of receptor occupancy by neuroleptics drugs; serotonin (5-hydroxytryptamine, 5-HT) receptors and the 5-HT transporter in affective disorders and for assessment of activity of antidepressants; nicotinic receptors and acetylcholinesterase as markers of cognitive and memory impairment; central benzodiazepine-binding sites at the γ-aminobutyric acid A (GABAA) receptor complex as markers of neuronal integrity in neurodegenerative disorders, epilepsy, and stroke and as the site of action of benzodiazepines; peripheral benzodiazepine receptors as indicators of inflammatory changes; opioid receptors detecting increased cortical excitability in focal epilepsy but also affected in perception of and emotional response to pain; and several receptor systems affected in drug abuse and craving. Further studies of the various transmitter/receptor systems and their balance and infraction will improve our understanding of complex brain functions and will provide more insight into the pathophysiol. of neurol. and psychiatric disease interaction.376Ouchi, Y.; Yoshikawa, E.; Futatsubashi, M.; Yagi, S.; Ueki, T.; Nakamura, K. Altered brain serotonin transporter and associated glucose metabolism in Alzheimer disease. J. Nucl. Med. 2009, 50, 1260– 1266, DOI: 10.2967/jnumed.109.063008[Crossref], [PubMed], [CAS], Google Scholar376https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrovVSnsg%253D%253D&md5=c71bbd3861c12f6c1e2c829970d8c08fAltered brain serotonin transporter and associated glucose metabolism in Alzheimer diseaseOuchi Yasuomi; Yoshikawa Etsuji; Futatsubashi Masami; Yagi Shunsuke; Ueki Takatoshi; Nakamura KazuhikoJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2009), 50 (8), 1260-6 ISSN:0161-5505.UNLABELLED: Whether preclinical depression is one of the pathophysiologic features of Alzheimer disease (AD) has been under debate. In vivo molecular imaging helps clarify this kind of issue. Here, we examined in vivo changes in the brain serotoninergic system and glucose metabolism by scanning early- to moderate-stage AD patients with and without depression using PET with a radiotracer for the serotonin transporter, (11)C-3-amino-4-(2-dimethylaminomethylphenylsulfanyl) benzonitrile (DASB), and a metabolic marker, (18)F-FDG. METHODS: Fifteen AD patients (8 nondepressed and 7 depressed) and 10 healthy subjects participated. All participants underwent 3-dimensional MRI and quantitative (11)C-DASB PET measurements, followed by (18)F-FDG PET scans in the AD group. Region-of-interest analysis was used to examine changes in (11)C-DASB binding potential estimated quantitatively by the Logan plot method in the serotonergic projection region. In addition, statistical parametric mapping was used to examine whether glucose metabolism in any brain region correlated with levels of (11)C-DASB binding in the dense serotonergic projection region (striatum) in AD. RESULTS: Psychologic evaluation showed that general cognitive function (Mini-Mental State Examination) was similar between the 2 AD subgroups. Striatal (11)C-DASB binding was significantly lower in AD patients, irrespective of depression, than in healthy controls (P < 0.05, corrected), and (11)C-DASB binding in other dense projection areas decreased significantly in the depressive group, compared with the control group. The (11)C-DASB binding potential levels in the subcortical serotonergic projection region correlated negatively with depression score (Spearman correlation, P < 0.01) but not with dementia score. Statistical parametric mapping correlation analysis showed that glucose metabolism in the right dorsolateral prefrontal cortex was positively associated with the level of striatal (11)C-DASB binding in AD. CONCLUSION: The significant reduction in (11)C-DASB binding in nondepressed AD patients suggests that presynaptic serotonergic function is altered before the development of psychiatric problems such as depression in AD. The depressive AD group showed greater and broader reductions in binding, suggesting that a greater loss of serotonergic function relates to more severe psychiatric symptoms in the disease. This serotonergic dysfunction may affect the activity of the right dorsolateral prefrontal cortex, a higher center of cognition and emotion in AD.377Meyer, J. H. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J. Psychiatry Neurosci. 2007, 32, 86– 102[PubMed], [CAS], Google Scholar377https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7ltlGhsg%253D%253D&md5=33a3b6568fcdeedb13d204ee02e4131aImaging the serotonin transporter during major depressive disorder and antidepressant treatmentMeyer Jeffrey HJournal of psychiatry & neuroscience : JPN (2007), 32 (2), 86-102 ISSN:1180-4882.This paper focuses on serotonin transporter 5-HTT imaging to investigate major depressive disorder (MDD) and antidepressant occupancy. Such investigations have only recently been possible as a result of major advances in ligand development. The state of the art method is [11C]DASB PET or [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) positron emission tomography. [11C]DASB is a breakthrough for brain imaging 5-HTT. Compared with previous radioligands, [11C]DASB offers both high selectivity and a favourable ratio of specific binding relative to free and nonspecific binding. These characteristics contribute to valid, reliable quantitation of the 5-HTT binding potential (BP). The 5-HTT BP can be viewed as an index of 5-HTT density in a medication free state, or unblocked 5-HTT density in a medication-treated state. During major depressive episodes with no other axis I comorbidity, either no difference in regional 5-HTT BP or a trend toward elevated 5-HTT BP is typically found. During major depressive episodes (of MDD) with more severe symptoms of pessimism (dysfunctional attitudes), regional 5-HTT BP is elevated. In subjects with major depressive episodes and comorbid axis I psychiatric illnesses, decreased regional 5-HTT BP is often reported. With selective serotonin reuptake inhibitor (SSRI) treatment at doses that distinguish from placebo in the treatment of major depressive episodes, 5-HTT occupancy is approximately 80%, and there is a strong relation between plasma level and occupancy that is not predictable based on affinity alone. Implications of 5-HTT imaging findings for understanding major depressive disorder and antidepressant treatment will be discussed.378Chugani, D. C.; Heyes, M. P.; Kuhn, D. M.; Chugani, H. T. Evidence that α[C-11]methyl-L-tryptophan PET traces tryptophan metabolism via the kynurenine pathway in tuberous sclerosis complex. Soc. Neurosci. Abstr. 1998, 24, 1757, 10010101150379Kumar, A.; Asano, E.; Chugani, H. T. α-[11C]-methyl- L -tryptophan PET for tracer localization of epileptogenic brain regions: Clinical studies. Biomarkers Med. 2011, 5, 577– 584, DOI: 10.2217/bmm.11.68[Crossref], [PubMed], [CAS], Google Scholar379https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlerurvK&md5=c1a5c94ea4ec8a2036aa38a0236c6a89α-[11C]-methyl-L-tryptophan PET for tracer localization of epileptogenic brain regions: clinical studiesKumar, Ajay; Asano, Eishi; Chugani, Harry T.Biomarkers in Medicine (2011), 5 (5), 577-584CODEN: BMIEDG; ISSN:1752-0363. (Future Medicine Ltd.)A review. Of several mol. probes used in PET, only α-[11C]-methyl-L-tryptophan (AMT) is able to pinpoint the epileptic focus itself in the interictal state, by revealing a focus of increased AMT uptake, even when an MRI or glucose metab. PET demonstrates normal findings. AMT PET appears to be particularly useful in patients with tuberous sclerosis complex and in patients with cortical developmental malformations. Although the sensitivity of AMT PET in finding the epileptic focus is about 70%, its specificity is almost 100%, indicating that if AMT PET identifies an area of increased uptake, it likely represents the epileptic focus which needs to be resected for better surgical outcome. In nontuberous sclerosis complex patients with cortical dysplasia, increased AMT uptake is usually assocd. with cortical dysplasia type IIB and a very good surgical outcome. Previously, no imaging modality has been able to predict the exact pathol. subtype or differentiate between epileptogenic and nonepileptogenic lesions interictally. The neuropathol. similarities between tubers and type IIB cortical dysplasia suggest a common mechanism of epilepsy, for which AMT PET is a biomarker. Due to the limited access to AMT PET, as presently it is labeled with 11C, which has a half-life of only 20 min and therefore has to be synthesized on site using a cyclotron, most of the AMT experience has originated primarily from only two centers. Therefore, there is a need for more clin. studies from other centers and this can be greatly facilitated if AMT can be labeled with 18F, a PET radionuclide widely available with a half-life of 110 min.380Kagawa, K.; Chugani, D. C.; Asano, E.; Juhász, C.; Muzik, O.; Shah, A.; Shah, J.; Sood, S.; Kupsky, W. J.; Mangner, T. J.; Chakraborty, P. K.; Chugani, H. T. Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). J. Child Neurol. 2005, 20, 429– 438, DOI: 10.1177/08830738050200050701[Crossref], [PubMed], [CAS], Google Scholar380https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2Mzit1Smug%253D%253D&md5=a4963dd5e72c9098c36dd59e13da388fEpilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET)Kagawa Kenji; Chugani Diane C; Asano Eishi; Juhasz Csaba; Muzik Otto; Shah Aashit; Shah Jagdish; Sood Sandeep; Kupsky William J; Mangner Thomas J; Chakraborty Pulak K; Chugani Harry TJournal of child neurology (2005), 20 (5), 429-38 ISSN:0883-0738.Tuberous sclerosis complex is commonly associated with medically intractable seizures. We previously demonstrated that high uptake of alpha-[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) occurs in a subset of epileptogenic tubers consistent with the location of seizure focus. In the present study, we analyzed the surgical outcome of children with tuberous sclerosis complex in relation to AMT PET results. Seventeen children (mean age 4.7 years) underwent epilepsy surgery, guided by long-term videoelectroencephalography (EEG) (including intracranial EEG in 14 cases), magnetic resonance imaging (MRI), and AMT PET. AMT uptake values of cortical tubers were measured using regions of interest delineated on coregistered MRI and were divided by the value for normal-appearing cortex to obtain an AMT uptake ratio. Based on surgical outcome data, tubers showing increased AMT uptake (uptake ratio greater than 1.00) were classified into three categories: (1) epileptogenic (tubers within an EEG-defined epileptic focus whose resection resulted in seizure-free outcome), (2) nonepileptogenic (tubers that were not resected but the patient became seizure free), or (3) uncertain (all other tubers). Increased AMT uptake was found in 30 tubers of 16 children, and 23 of these tubers (77%) were located in an EEG-defined epileptic focus. The tuber with the highest uptake was located in an ictal EEG onset region in each patient. Increased AMT uptake indicated an epileptic region not suspected by scalp EEG in four cases. Twelve children (71%) achieved seizure-free outcome (median follow-up 15 months). Based on outcome criteria, 19 of 30 tubers (63%) with increased AMT uptake were epileptogenic, and these tubers had significantly higher AMT uptake than the nonepileptogenic ones (P = .009). Tubers with at least 10% increase of AMT uptake (in nine patients) were all epileptogenic. Using a cutoff threshold of 1.02 for AMT uptake ratio provided an optimal accuracy of 83% for detecting tubers that needed to be resected to achieve a seizure-free outcome. The findings suggest that resection of tubers with increased AMT uptake is highly desirable to achieve seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery.381Wakamoto, H.; Chugani, D. C.; Juhász, C.; Muzik, O.; Kupsky, W. J.; Chugani, H. T. Alpha-methyl-l-tryptophan positron emission tomography in epilepsy with cortical developmental malformations. Pediatric Neurology. 2008, 39, 181– 188, DOI: 10.1016/j.pediatrneurol.2008.05.014[Crossref], [PubMed], [CAS], Google Scholar381https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnivFGisw%253D%253D&md5=b1739c28aa40510e70cd143e701dd3d9Alpha-methyl-l-tryptophan positron emission tomography in epilepsy with cortical developmental malformationsWakamoto Hiroyuki; Chugani Diane C; Juhasz Csaba; Muzik Otto; Kupsky William J; Chugani Harry TPediatric neurology (2008), 39 (3), 181-8 ISSN:0887-8994.Preliminary studies suggest that alpha[(11)C]methyl-l-tryptophan positron emission tomography can detect the epileptic focus within malformations of cortical development. We determined the sensitivity and specificity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography in identifying epileptic focus in children with intractable, neocortical epilepsy with and without malformations of cortical development. Seventy-three epileptic children were classified into lesional and nonlesional groups, and compared regarding focal increased alpha-[(11)C]methyl-l-tryptophan uptake. The sensitivity and specificity of focal increased alpha-[(11)C]methyl-l-tryptophan uptake, using intracranial electroencephalogram localization of seizure onset as the standard, were compared between lesional and nonlesional groups. The specificity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography for detecting seizure onset lobe was equally high in lesional (97%) and nonlesional groups (100%), whereas sensitivity was higher in the lesional than the nonlesional group (47% versus 29%; P = 0.047). The incidence of alpha-[(11)C]methyl-l-tryptophan uptake abnormality was higher in the lesional than the nonlesional group (P < 0.01). Alpha-[(11)C]methyl-l-tryptophan positron emission tomography localized and visualized epileptogenic regions in 25% of patients with nonlocalizing magnetic resonance imaging. Although overall sensitivity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography in identifying neocortical epileptic focus is modest, specificity is extremely high. When an alpha-[(11)C]methyl-l-tryptophan focus is detected, it likely represents the epileptogenic region to be resected.382Chugani, H. T.; Kumar, A.; Kupsky, W.; Asano, E.; Sood, S.; Juhász, C. Clinical and histopathologic correlates of 11C-alpha-methyl-l-tryptophan (AMT) PET abnormalities in children with intractable epilepsy: Histopathologic correlates of AMT-PET. Epilepsia 2011, 52, 1692– 1698, DOI: 10.1111/j.1528-1167.2011.03103.x[Crossref], [PubMed], [CAS], Google Scholar382https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht12ktLzP&md5=8de99c427312dbc013c4aebc933b5adbClinical and histopathologic correlates of IIC-alpha-methyl-L-tryptophan (AMT) PET abnormalities in children with intractable epilepsyChugani, Harry T.; Kumar, Ajay; Kupsky, William; Asano, Eishi; Sood, Sandeep; Juhasz, CsabaEpilepsia (2011), 52 (9), 1692-1698CODEN: EPILAK; ISSN:0013-9580. (Wiley-Blackwell)Purpose: Interictal increase of 11C-alpha-methyl-L-tryptophan (AMT) on positron emission tomog. (PET) can be seen in cortical epileptic foci, and is particularly common in cortical developmental malformations. Therefore, in the present study, we evaluated the clin. and histopathol. correlates of AMT-PET abnormalities in children with intractable epilepsy undergoing resp. surgery. Methods: Thirty children (mean age: 6.7 ± 3.2 years) were included in this study. All patients received AMT-PET as part of their presurgical evaluation and subsequently underwent epilepsy surgery. Magnetic resonance imaging (MRI) scans were normal in 15, showed nonspecific changes in 8, and suggested malformations of cortical development (MCDs) in nine children. Asymmetry indexes (AIs) were calcd. to det. increased AMT uptake. Key Findings: Histopathol. revealed MCDs in 16 (53%) children, including 12 with cortical dysplasia (CD) [mild MCD = 3; CD type IA = 2; CD type IIA = 2 and CD type MB (severe CD with balloon cells) = 5]. Polymicrogyria and heterotopias (P&Hs) were seen in three cases and subependymal heterotopias (SEHs) in one child. The remaining 14 cases showed normal histopathol. with varying degrees of gliosis. Increased AMT uptake was found in all five with CD type MB, and all three with P&H, but in none with mild MCD and types IA-IIA CD or SEH. Whereas all five children with CD IIB and two with P&H had excellent surgical outcome (class I); children with milder CD or SEH had variable surgical outcome. The 14 patients with normal histopathol. included seven patients with focally increased and seven with normal AMT uptake. Although patients with normal pathol. and normal AMT-PET had better surgical outcome (class I = 5; II = 2), those with normal pathol., normal MRI, but abnormal AMT-PET had poor surgical outcome (class III = 4; IV = 3). Significance: Increased AMT uptake in children with CD may predict type IIB dysplasia (with balloon cells) and good surgical outcome. Histopathol. similarities between CD type IIB and epileptogenic cortical tubers may imply a common role of the inflammatory kynurenine pathway of tryptophan metab. in these lesions. In children with normal histopathol., there is a subgroup with increased AMT uptake and poor surgical outcome.383Thompson, A. J.; Metzger, S.; Lochner, M.; Ruepp, M.-D. The binding orientation of epibatidine at A7 nACh receptors. Neuropharmacology 2017, 116, 421– 428, DOI: 10.1016/j.neuropharm.2017.01.008[Crossref], [PubMed], [CAS], Google Scholar383https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslels70%253D&md5=addcf5c00648522ca36ec7e15d38e40bThe binding orientation of epibatidine at α7 nACh receptorsThompson, Andrew J.; Metzger, Simon; Lochner, Martin; Ruepp, Marc-DavidNeuropharmacology (2017), 116 (), 421-428CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)Epibatidine is an alkaloid toxin that binds with high affinity to nicotinic and muscarinic acetylcholine receptors, and has been extensively used as a research tool. To examine binding interactions at the nicotinic receptor, it has been co-crystd. with the structural homolog acetylcholine binding protein (AChBP; PDB ID 2BYQ), and with an AChBP chimaera (3SQ6) that shares 64% sequence identity with the α7 nACh receptor. However, the binding orientations revealed by AChBP co-crystal structures may not precisely represent their receptor homologues and exptl. evidence is needed to verify the ligand poses. Here we identify potential binding site interactions between epibatidine and AChBP residues, and substitute equiv. positions in the α7 nACh receptor. The effects of these are probed by [3H]epibatidine binding following the expression α7 nACh receptor cysteine mutants in HEK 293 cells. Of the sixteen mutants created, the affinity of epibatidine was unaffected by the substitutions Q55C, L106C, L116C, T146C, D160C and S162C, reduced by C186A and C187A, increased by Q114C and S144C, and abolished by W53C, Y91C, N104C, W145C, Y184C and Y191C. These results are consistent with the predicted orientations in AChBP and suggest that epibatidine is likely to occupy a similar location at α7 nACh receptors. We speculate that steric constraints placed upon the C-5 position of the pyridine ring in 3SQ6 may account for the relatively poor affinities of epibatidine derivs. that are substituted at this position.384Wong, D. F.; Kuwabara, H.; Pomper, M.; Holt, D. P.; Brasic, J. R.; George, N.; Frolov, B.; Willis, W.; Gao, Y.; Valentine, H.; Nandi, A.; Gapasin, L.; Dannals, R. F.; Horti, A. G. Human brain imaging of A7 nAChR with [18F]ASEM: A new PET radiotracer for neuropsychiatry and determination of drug occupancy. Mol. Imaging Biol. 2014, 16, 730– 738, DOI: 10.1007/s11307-014-0779-3[Crossref], [PubMed], [CAS], Google Scholar384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252Fkt1Ghug%253D%253D&md5=3cf858ba37824e3fe52efcbaae0d6572Human brain imaging of α7 nAChR with [(18)F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancyWong Dean F; Kuwabara Hiroto; Pomper Martin; Holt Daniel P; Brasic James R; George Noble; Frolov Boris; Willis William; Gao Yongjun; Valentine Heather; Nandi Ayon; Gapasin Lorena; Dannals Robert F; Horti Andrew GMolecular imaging and biology (2014), 16 (5), 730-8 ISSN:.PURPOSE: Using the α7-nAChR radiotracer, [(18)F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer. PROCEDURES: Five healthy male subjects were imaged for 90 min following IV [(18)F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [(18)F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding. RESULTS: [(18)F]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [(18)F]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (>20 ml/ml) and binding potentials >1 with TRV averaged 10.8 ± 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two α7-nAChR drugs. CONCLUSIONS: The characteristics of [(18)F]ASEM are consistent with the ability to quantify α7-nAChR in the human brain. [(18)F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential α7-nAChR drugs.385Horti, A. G. Development of [(18)F]ASEM, a specific radiotracer for quantification of the A7-nAChR with positron-emission tomography. Biochem. Pharmacol. 2015, 97, 566– 575, DOI: 10.1016/j.bcp.2015.07.030[Crossref], [PubMed], [CAS], Google Scholar385https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Oqt7vN&md5=1cf3d50ab569d38a65bec2d097d6c56fDevelopment of [18F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomographyHorti, A. G.Biochemical Pharmacology (Amsterdam, Netherlands) (2015), 97 (4), 566-575CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)A review. The alpha-7 subtype of the nicotinic acetylcholine receptor (α7-nAChR) is fundamental to physiol.; it mediates various brain functions and represents an important target for drug discovery. Exploration of the brain nicotinic acetylcholine receptors (nAChRs) using positron-emission tomog. (PET) will make it possible to better understand the important role of this receptor and to study its involvement in schizophrenia, bipolar disorder, Alzheimer's and Parkinson's diseases, drug dependence, inflammation and many other disorders and simplify the development of nicotinic drugs for treatment of these disorders. Until recently, PET imaging of α7-nAChRs has been impeded by the absence of good radiotracers. This review describes various endeavors to develop α7-nAChR PET tracers by several research groups including the author's group. Most initial PET tracers for imaging α7-nAChRs did not exhibit suitable imaging properties due to their low specific binding. Newly discovered [18F]ASEM is the first highly specific α7-nAChR radioligand and in 2014 it was translated to human PET imaging.386Zubieta, J. K.; Koeppe, R. A.; Frey, K. A.; Kilbourn, M. R.; Mangner, T. J.; Foster, N. L.; Kuhl, D. E. Assessment of muscarinic receptor concentrations in aging and Alzheimer disease with [11C]NMPB and PET. Synapse 2001, 39, 275– 287, DOI: 10.1002/1098-2396(20010315)39:4<275::AID-SYN1010>3.0.CO;2-3[Crossref], [PubMed], [CAS], Google Scholar386https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhtVGntb8%253D&md5=59fcb4d5a8eab599343a983374280739Assessment of muscarinic receptor concentrations in aging and Alzheimer disease with [11C]NMPB and PETZubieta, Jon-Kar; Koeppe, Robert A.; Frey, Kirk A.; Kilbourn, Michael R.; Mangner, Thomas J.; Foster, Norman L.; Kuhl, David E.Synapse (New York) (2001), 39 (4), 275-287CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)Cerebral cholinergic deficits have been described in Alzheimer disease (AD) and as a result of normal aging. At the present time, there are very limited options for the quantification of cholinergic receptors with in vivo imaging techniques such as PET. In the present study, we examd. the feasibility of utilizing [11C]N-methyl-4-piperidyl benzilate (NMPB), a nonselective muscarinic receptor ligand, in the study of aging and neurodegenerative processes assocd. with cholinergic dysfunction. Based on prior data describing the accuracy of various kinetic methods, we examd. the concn. of muscarinic receptors with [11C]NMPB and PET using two- and three- compartment kinetic models. Eighteen healthy subjects and six patients diagnosed with probable AD were studied. Pixel-by-pixel two-compartment model fits showed acceptable precision in the study of normal aging, with comparable results to those obtained with a more complex and less precise three-compartment model. Normal aging was assocd. with a redn. in muscarinic receptor binding in neocortical regions and thalamus. In AD patients, the three-compartment model appeared capable of dissocg. changes in tracer transport from changes in receptor binding, but suffered from statistical uncertainty, requiring normalization to a ref. region, and therefore limiting its potential use in the study of neurodegenerative processes. After normalization, no regional changes in muscarinic receptor concns. were obsd. in AD.387Asahina, M.; Suhara, T.; Shinotoh, H.; Inoue, O.; Suzuki, K.; Hattori, T. Brain muscarinic receptors in progressive supranuclear palsy and Parkinson’s disease: A positron emission tomographic study. J. Neurol., Neurosurg. Psychiatry 1998, 65, 155– 163, DOI: 10.1136/jnnp.65.2.155[Crossref], [PubMed], [CAS], Google Scholar387https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1czms1Ohtg%253D%253D&md5=aa4e24971e6dcf287f06236c9e9bbe94Brain muscarinic receptors in progressive supranuclear palsy and Parkinson's disease: a positron emission tomographic studyAsahina M; Suhara T; Shinotoh H; Inoue O; Suzuki K; Hattori TJournal of neurology, neurosurgery, and psychiatry (1998), 65 (2), 155-63 ISSN:0022-3050.OBJECTIVES: To assess muscarinic acetylcholine receptors (mAChRs) in the brains of patients with progressive supranuclear palsy and Parkinson's disease, and to correlate the cholinergic system with cognitive function in progressive supranuclear palsy and Parkinson's disease. METHODS: Positron emission tomography (PET) and [11C]N-methyl-4-piperidyl benzilate ([11C]NMPB) was used to measure mAChRs in the brain of seven patients with progressive supranuclear palsy, 12 patients with Parkinson's disease, and eight healthy controls. All of the patients with progressive supranuclear palsy were demented. The Parkinson's disease group consisted of 11 non-demented patients and one demented patient. The mini mental state examination (MMSE) was used to assess the severity of cognitive dysfunction in all of the subjects. The modified Wisconsin card sorting test (WCST) was used to evaluate frontal cognitive function in the non-demented patients with Parkinson's disease and controls. RESULTS: The mean K3 value, an index of mAChR binding, was significantly higher for the frontal cortex in the patients with Parkinson's disease than in the controls (p<0.01). By contrast, the patients with progressive supranuclear palsy had no significant changes in the K3 values of any cerebral cortical regions. The mean score of the MMSE in the progressive supranuclear palsy group was significantly lower than that in the control group. Although there was no difference between the Parkinson's disease and control groups in the MMSE, the non-demented patients with Parkinson's disease showed significant frontal lobe dysfunction in the WCST. CONCLUSIONS: The increased mAChR binding in the frontal cortex of the patients with Parkinson's disease may reflect denervation hypersensitivity caused by loss of the ascending cholinergic input to that region from the basal forebrain and may be related to frontal lobe dysfunction in Parkinson's disease. The cerebral cortical cholinergic system may not have a major role in cognitive dysfunction in progressive supranuclear palsy.388Pappata, S.; Tavitian, B.; Traykov, L.; Jobert, A.; Dalger, A.; Mangin, J. F.; Crouzel, C.; DiGiamberardino, L. In vivo imaging of human cerebral acetylcholinesterase. J. Neurochem. 1996, 67, 876– 879, DOI: 10.1046/j.1471-4159.1996.67020876.x[Crossref], [PubMed], [CAS], Google Scholar388https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XksFCjtbs%253D&md5=38bfe3946ffe3bd7007f6ec269602a04In vivo imaging of human cerebral acetylcholinesterasePappata, S.; Tavitian, B.; Traykov, L.; Jobert, A.; Dalger, A.; Mangin, J. F.; Crouzel, C.; Di Giamberardino, L.Journal of Neurochemistry (1996), 67 (2), 876-879CODEN: JONRA9; ISSN:0022-3042. (Lippincott-Raven)We report here the first positron emission tomog. (PET) images showing the in vivo regional distribution of acetylcholinesterase (AChE) in human brain. The study was carried out in eight healthy human volunteers using as a tracer [11C]-physostigmine ([11C]PHY), an inhibitor of AChE. After i.v. injection of [11C]PHY, radioactivity was rapidly taken up in brain tissue and reached maximal uptake within a few minutes, following a regional pattern mostly related to cerebral perfusion. After the peak, the cerebral radioactivity gradually decreased with a half-life varying from 20 to 35 min, depending on the brain structure. [11C]PHY retention was higher in regions rich in AChE, such as the striatum (half-life, 35 min), than in regions poor in AChE, such as the cerebral cortex (half-life, 20 min). At later times (25-35 min postinjection), the cerebral distribution of [11C]PHY was typical of AChE activity: putamen-caudate > cerebellum > brainstem > thalamus > cerebral cortex, with a striatal to cortex ratio of 2. These results suggest that PET studies with [11C]PHY can provide in vivo brain mapping of human AChE and are promising for the study of changes in AChE levels assocd. with neurodegenerative diseases.389Herholz, K. Acetylcholine esterase activity in mild cognitive impairment and Alzheimer’s Disease. Eur. J. Nucl. Med. Mol. Imaging 2008, 35 (S1), 25– 29, DOI: 10.1007/s00259-007-0699-4[Crossref], [CAS], Google Scholar389https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlsFOitLY%253D&md5=613218420bb4f2bc667fdfe675a30c4bAcetylcholine esterase activity in mild cognitive impairment and Alzheimer's diseaseHerholz, KarlEuropean Journal of Nuclear Medicine and Molecular Imaging (2008), 35 (Suppl. 1), S25-S29CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. Purpose: Impairment of cholinergic neurotransmission is a well-established fact in Alzheimer's disease (AD), but there is controversy about its relevance at the early stages of the disease and in mild cognitive impairment (MCI). Methods: In vivo positron emission tomog. imaging of cortical acetylcholine esterase (AChE) activity as a marker of cholinergic innervation that is expressed by cholinergic axons and cholinoceptive neurons has demonstrated a redn. of this enzyme activity in manifest AD. The technique is also useful to measure the inhibition of cerebral AChE induced by cholinesterase inhibitors for treatment of dementia symptoms. Results: A redn. of cortical AchE activity was found consistently in all studies of AD and in few cases of MCI who later concerted to AD. Conclusion: The in vivo findings in MCI and very mild AD are still preliminary, and studies seem to suggest that cholinergic innervation and AChE as the main degrading enzyme are both reduced, which might result in partial compensation of their effect.390Mathis, C. A.; Bacskai, B. J.; Kajdasz, S. T.; McLellan, M. E.; Frosch, M. P.; Hyman, B. T.; Holt, D. P.; Wang, Y.; Huang, G.-F.; Debnath, M. L.; Klunk, W. E. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg. Med. Chem. Lett. 2002, 12, 295– 298, DOI: 10.1016/S0960-894X(01)00734-X[Crossref], [PubMed], [CAS], Google Scholar390https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpslKmtQ%253D%253D&md5=c761b7a60b9ec39bdf615c28983a89e0A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brainMathis, Chester A.; Bacskai, Brian J.; Kajdasz, Stephen T.; McLellan, Megan E.; Frosch, Matthew P.; Hyman, Bradley T.; Holt, Daniel P.; Wang, Yanming; Huang, Guo-Feng; Debnath, Manik L.; Klunk, William E.Bioorganic & Medicinal Chemistry Letters (2002), 12 (3), 295-298CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The synthesis of a new lipophilic thioflavin-T analog, 2-[4-(methylamino)phenyl]benzothiazole (I), with high affinity for amyloid is reported. I.v. injection of [11C]-labeled I into control mice resulted in high brain uptake. Amyloid deposits were imaged with multiphoton microscopy in the brains of living transgenic mice following the systemic injection of unlabeled I. [11C]-I is a promising amyloid imaging agent for Alzheimer's disease.391Grimmer, T.; Shi, K.; Diehl-Schmid, J.; Natale, B.; Drzezga, A.; Förster, S.; Förstl, H.; Schwaiger, M.; Yakushev, I.; Wester, H.-J.; Kurz, A.; Yousefi, B. H. Correction: 18F-FIBT may expand PET for β-amyloid imaging in neurodegenerative diseases. Mol. Psychiatry 2020, 25, 2608– 2619, DOI: 10.1038/s41380-018-0203-5[Crossref], [PubMed], [CAS], Google Scholar391https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFCktbzL&md5=0af5e6b6cbc45cfeb0547e22eb93333418F-FIBT may expand PET for β-amyloid imaging in neurodegenerative diseasesGrimmer, Timo; Shi, Kuangyu; Diehl-Schmid, Janine; Natale, Bianca; Drzezga, Alexander; Foerster, Stefan; Foerstl, Hans; Schwaiger, Markus; Yakushev, Igor; Wester, Hans-Juergen; Kurz, Alexander; Yousefi, Behrooz HooshyarMolecular Psychiatry (2020), 25 (10), 2608-2619CODEN: MOPSFQ; ISSN:1359-4184. (Nature Research)18F-FIBT, 2-(p-Methylaminophenyl)-7-(2-[18F]fluoroethoxy)imidazo-[2,1-b]benzothiazole, is a new selective PET tracer under clin. investigation to specifically image β-amyloid depositions (Aβ) in humans in-vivo that binds to Aβ with excellent affinity (Kd 0.7 ± 0.2) and high selectivity over tau and α-synuclein aggregates (Ki > 1000 nM). We aimed to characterize 18F-FIBT in a series of patients with different clin.-pathophysiol. phenotypes and to compare its binding characteristics to the ref. compd. PiB. Six patients (mild late-onset and moderate early-onset AD dementia, mild cognitive impairment due to AD, intermediate likelihood, mild behavioral variant of frontotemporal dementia, subjective memory impairment without evidence of neurodegeneration, and mild dementia due to Posterior Cortical Atrophy) underwent PET imaging with 18F-FIBT on PET/MR. SUVR showed the highest correlation with clin. severity. The previous preclin. characterization and the results of this case series suggest the clin. usefulness of FIBT as a selective and highly affine next-generation 18F-labeled tracer for amyloid-imaging with excellent pharmacokinetics in the diagnosis of neurodegenerative diseases. The results compare well to the gold std. PiB and hence support further investigation in larger human samples.392Richards, D.; Sabbagh, M. N. Florbetaben for PET imaging of beta-amyloid plaques in the brain. Neurol Ther. 2014, 3, 79– 88, DOI: 10.1007/s40120-014-0022-9[Crossref], [PubMed], [CAS], Google Scholar392https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfmsFWrsw%253D%253D&md5=473d2268da9f93443d7b9e1f3c843209Florbetaben for PET Imaging of Beta-Amyloid Plaques in the BrainRichards Danielle; Sabbagh Marwan NNeurology and therapy (2014), 3 (2), 79-88 ISSN:2193-8253.Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting the elderly. Current clinical diagnostic tools are often ineffective in accurately diagnosing AD. However, new advances in diagnostic imaging, particularly positron emission tomography (PET) amyloid imaging, have shown increased sensitivity and specificity, as well as high inter-reader agreement. The most commonly studied tracer, PiB-C11, has shown high affinity binding to amyloid, but is limited in its use outside of research due to its short half-life. Instead, development of other PET ligands with increased half-life, such as fluorine-18-labeled ((18)F) tracers, allows for more widespread use of PET in clinical settings. In particular, recent phase II and III trials of (18)F-florbetaben have demonstrated the high accuracy of this PET tracer in identifying amyloid accumulation. This paper will examine the techniques of amyloid imaging, focusing particularly on the recently approved (18)F-florbetaben.393Klunk, W. E.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; Holt, D. P.; Bergström, M.; Savitcheva, I.; Huang, G.; Estrada, S.; Ausén, B.; Debnath, M. L.; Barletta, J.; Price, J. C.; Sandell, J.; Lopresti, B. J.; Wall, A.; Koivisto, P.; Antoni, G.; Mathis, C. A.; Långström, B. Imaging brain amyloid in Alzheimer’s Disease with Pittsburgh compound-B. Ann. Neurol. 2004, 55, 306– 319, DOI: 10.1002/ana.20009[Crossref], [PubMed], [CAS], Google Scholar393https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisFKntb8%253D&md5=3e036dca56dcb81e0cf131a5b100f95fImaging brain amyloid in Alzheimer's disease with Pittsburgh compound-BKlunk, William E.; Engler, Henry; Nordberg, Agneta; Wang, Yanming; Blomqvist, Gunnar; Holt, Daniel P.; Bergstrom, Mats; Savitcheva, Irina; Huang, Guo-feng; Estrada, Sergio; Ausen, Birgitta; Debnath, Manik L.; Barletta, Julien; Price, Julie C.; Sandell, Johan; Lopresti, Brian J.; Wall, Anders; Koivisto, Pernilla; Antoni, Gunnar; Mathis, Chester A.; Langstrom, BengtAnnals of Neurology (2004), 55 (3), 306-319CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)This report describes the first human study of a novel amyloid-imaging positron emission tomog. (PET) tracer, termed Pittsburgh Compd.-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of assocn. cortex known to contain large amts. of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were obsd. in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equiv. in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 yr) and six older healthy controls (69.5±11 yr) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metab. detd. with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quant. information on amyloid deposits in living subjects.394Wolk, D. A.; Zhang, Z.; Boudhar, S.; Clark, C. M.; Pontecorvo, M. J.; Arnold, S. E. Amyloid imaging in Alzheimer’s disease: Comparison of florbetapir and Pittsburgh compound-B positron emission tomography. J. Neurol., Neurosurg. Psychiatry 2012, 83, 923– 926, DOI: 10.1136/jnnp-2012-302548[Crossref], [PubMed], [CAS], Google Scholar394https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jpslCrug%253D%253D&md5=930cb64494f5292f869e9f01e5463e62Amyloid imaging in Alzheimer's disease: comparison of florbetapir and Pittsburgh compound-B positron emission tomographyWolk David A; Zhang Zheng; Boudhar Sanaa; Clark Christopher M; Pontecorvo Michael J; Arnold Steven EJournal of neurology, neurosurgery, and psychiatry (2012), 83 (9), 923-6 ISSN:.BACKGROUND: Amyloid imaging provides in vivo detection of the fibrillar amyloid-β (Aβ) plaques of Alzheimer's disease (AD). The positron emission tomography (PET) ligand, Pittsburgh Compound-B (PiB-C11), is the most well studied amyloid imaging agent, but the short half-life of carbon-11 limits its clinical viability. Florbetapir-F18 recently demonstrated in vivo correlation with postmortem Aβ histopathology, but has not been directly compared with PiB-C11. METHODS: Fourteen cognitively normal adults and 12 AD patients underwent PiB-C11 and florbetapir-F18 PET scans within a 28-day period. RESULTS: Both ligands displayed highly significant group discrimination and correlation of regional uptake. CONCLUSION: These data support the hypothesis that florbetapir-F18 provides comparable information with PiB-C11.395Vandenberghe, R.; Van Laere, K.; Ivanoiu, A.; Salmon, E.; Bastin, C.; Triau, E.; Hasselbalch, S.; Law, I.; Andersen, A.; Korner, A.; Minthon, L.; Garraux, G.; Nelissen, N.; Bormans, G.; Buckley, C.; Owenius, R.; Thurfjell, L.; Farrar, G.; Brooks, D. J. 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial. Ann. Neurol. 2010, 68, 319– 329, DOI: 10.1002/ana.22068[Crossref], [PubMed], [CAS], Google Scholar395https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cjpsleisg%253D%253D&md5=1cef58b91f2f25d7d48fef9d352c64b018F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trialVandenberghe Rik; Van Laere Koen; Ivanoiu Adrian; Salmon Eric; Bastin Christine; Triau Eric; Hasselbalch Steen; Law Ian; Andersen Allan; Korner Alex; Minthon Lennart; Garraux Gaetan; Nelissen Natalie; Bormans Guy; Buckley Chris; Owenius Rikard; Thurfjell Lennart; Farrar Gill; Brooks David JAnnals of neurology (2010), 68 (3), 319-29 ISSN:.OBJECTIVE: The most widely studied positron emission tomography ligand for in vivo beta-amyloid imaging is (11)C-Pittsburgh compound B ((11)C-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the (18)F-labeled PIB derivative (18)F-flutemetamol could significantly enhance access to this novel technology. METHODS: Twenty-seven patients with early-stage clinically probable Alzheimer disease (AD), 20 with amnestic mild cognitive impairment (MCI), and 15 cognitively intact healthy volunteers (HVs) above and 10 HVs below 55 years of age participated. The primary endpoint was the efficacy of blinded visual assessments of (18)F-flutemetamol scans in assigning subjects to a raised versus normal uptake category, with clinical diagnosis as the standard of truth (SOT). As secondary objectives, we determined the correlation between the regional standardized uptake value ratios (SUVRs) for (18)F-flutemetamol and its parent molecule (11)C-PIB in 20 of the AD subjects and 20 of the MCI patients. We also determined test-retest variability of (18)F-flutemetamol SUVRs in 5 of the AD subjects. RESULTS: Blinded visual assessments of (18)F-flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical (18)F-flutemetamol SUVRs and (11)C-PIB SUVRs ranged from 0.89 to 0.92. Test-retest variabilities of regional SUVRs were 1 to 4%. INTERPRETATION: (18)F-Flutemetamol performs similarly to the (11)C-PIB parent molecule within the same subjects and provides high test-retest replicability and potentially much wider accessibility for clinical and research use.396Rowe, C. C.; Villemagne, V. L. Brain amyloid imaging. J. Nucl. Med. Technol. 2013, 41, 11– 18, DOI: 10.2967/jnumed.110.076315[Crossref], [PubMed], [CAS], Google Scholar396https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3szntVKqsw%253D%253D&md5=da2dbc87cdcb299789fed14f7a1848b0Brain amyloid imagingRowe Christopher C; Villemagne Victor LJournal of nuclear medicine technology (2013), 41 (1), 11-8 ISSN:.Imaging of brain β-amyloid plaques with (18)F-labeled tracers for PET will likely be available in clinical practice to assist the diagnosis of Alzheimer disease (AD). With the rapidly growing prevalence of AD as the population ages, and the increasing emphasis on early diagnosis and treatment, brain amyloid imaging is set to become a widely performed investigation. All physicians reading PET scans will need to know the complex relationship between amyloid and cognitive decline, how to best acquire and display images for detection of amyloid, and how to recognize the patterns of tracer binding in AD and other causes of dementia. This article will provide nuclear medicine physicians with the background knowledge required for understanding this emerging investigation, including its appropriate use, and prepare them for practical training in scan interpretation.397Verhoeff, N. P. L. G. In-Vivo imaging of Alzheimer disease -amyloid with [11C]SB-13 PET. American Journal of Geriatric Psychiatry. 2004, 12, 584– 595, DOI: 10.1176/appi.ajgp.12.6.584[Crossref], [PubMed], [CAS], Google Scholar397https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cngtFOnsg%253D%253D&md5=2bcdcbabeecdb1c3668ea2d01bda5ac3In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PETVerhoeff Nicolaas P L G; Wilson Alan A; Takeshita Shinichiro; Trop Liat; Hussey Doug; Singh Kernjit; Kung Hank F; Kung Mei-Ping; Houle SylvainThe American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry (2004), 12 (6), 584-95 ISSN:1064-7481.OBJECTIVE: In-vivo imaging of beta-amyloid plaques (Abeta) may improve both early detection of Alzheimer disease (AD) and efficacy assessment of new treatments for AD. The authors' aim was to develop a novel Abeta-specific positron-emission tomography (PET) tracer. METHODS: Five female AD patients (54-77 years old) and six healthy female comparison subjects (53-74 years old), completed 2-hour PET scans after intravenous injection of 10 mCi of both the stilbene [11C]SB-13 and the benzothiazole [11C]6-OH-BTA-1 (also known as [11C]PIB). Kinetic analyses were performed on the resulting time-activity curves to derive Abeta binding-potential estimates, using as input function either the unmetabolized tracer concentration in venous plasma from a two-tissue compartment model or the density of radioactivity in the cerebellum. Authors compared the binding characteristics of the two radiotracers. RESULTS: The two radiotracers demonstrated similar binding properties with respect to regional distribution of retention (increased retention in the frontal and posterior temporal-inferior parietal association cortices in the AD patients, but not in the comparison subjects). Our preliminary PET data indicate that [11C]SB-13 may be similar to [11C]PIB in discriminating AD patients from comparison subjects. CONCLUSIONS: [11C]SB-13 is an effective PET tracer for fibrillar Abeta imaging in vivo, with similar performance as [11C]PIB. Future research directions include evaluation of tracer in larger AD patient samples and in subjects with amnestic mild cognitive impairment, evaluation of arterial input function, and comparison with other tracers, such as [18F]FDG as they relate to cognitive functioning.398Buée, L.; Bussière, T.; Buée-Scherrer, V.; Delacourte, A.; Hof, P. R. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Rev. 2000, 33, 95– 130, DOI: 10.1016/S0165-0173(00)00019-9[Crossref], [PubMed], [CAS], Google Scholar398https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtVCrtbY%253D&md5=d51d14c9e8b56e9661db4ae4afc2c943Tau protein isoforms, phosphorylation and role in neurodegenerative disordersBuee, L.; Bussiere, T.; Buee-Scherrer, V.; Delacourte, A.; Hof, P. R.Brain Research Reviews (2000), 33 (1), 95-130CODEN: BRERD2; ISSN:0165-0173. (Elsevier Science B.V.)A review, with 425 refs. Tau proteins belong to the family of microtubule-assocd. proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intra-neuronal and glial fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Mol. anal. has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathol. tau proteins exhibiting a typical biochem. pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathol. tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.399Lois, C.; Gonzalez, I.; Johnson, K. A.; Price, J. C. PET imaging of tau protein targets: A methodology perspective. Brain Imaging and Behavior. 2019, 13, 333– 344, DOI: 10.1007/s11682-018-9847-7[Crossref], [PubMed], [CAS], Google Scholar399https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MrntVagtg%253D%253D&md5=b83e6256f07ebfedf37a2e78748fe5d9PET imaging of tau protein targets: a methodology perspectiveLois Cristina; Johnson Keith A; Gonzalez Ivan; Price Julie CBrain imaging and behavior (2019), 13 (2), 333-344 ISSN:.The two neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-[Formula: see text] plaques and neurofibrillary tangles of tau protein. Fifteen years ago, Positron Emission Tomography (PET) with Pittsburgh Compound B ((11)C-PiB) enabled selective in-vivo visualization of amyloid-[Formula: see text] plaque deposits and has since provided valuable information about the role of amyloid-[Formula: see text] deposition in AD. The progression of tau deposition has been shown to be highly associated with neuronal loss, neurodegeneration, and cognitive decline. Until recently it was not possible to visualize tau deposition in-vivo, but several tau PET tracers are now available in different stages of clinical development. To date, no tau tracer has been approved by the Food and Drug Administration for use in the evaluation of AD or other tauopathies, despite very active research efforts. In this paper we review the recent developments in tau PET imaging with a focus on in-vivo findings in AD and discuss the challenges associated with tau tracer development, the status of development and validation of different tau tracers, and the clinical information these provide.400Giannakopoulos, P.; Herrmann, F. R.; Bussière, T.; Bouras, C.; Kövari, E.; Perl, D. P.; Morrison, J. H.; Gold, G.; Hof, P. R. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 2003, 60, 1495– 1500, DOI: 10.1212/01.WNL.0000063311.58879.01[Crossref], [PubMed], [CAS], Google Scholar400https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s3it1Sqtg%253D%253D&md5=7269baa47ff91be1243c2d7648335dd9Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's diseaseGiannakopoulos P; Herrmann F R; Bussiere T; Bouras C; Kovari E; Perl D P; Morrison J H; Gold G; Hof P RNeurology (2003), 60 (9), 1495-500 ISSN:.OBJECTIVE: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. BACKGROUND: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. METHODS: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. RESULTS: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. CONCLUSIONS: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.401Okamura, N.; Suemoto, T.; Furumoto, S.; Suzuki, M.; Shimadzu, H.; Akatsu, H.; Yamamoto, T.; Fujiwara, H.; Nemoto, M.; Maruyama, M.; Arai, H.; Yanai, K.; Sawada, T.; Kudo, Y. Quinoline and benzimidazole derivatives: Candidate probes for in vivo imaging of tau pathology in Alzheimer’s disease. J. Neurosci. 2005, 25, 10857– 10862, DOI: 10.1523/JNEUROSCI.1738-05.2005[Crossref], [PubMed], [CAS], Google Scholar401https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yks77K&md5=4b0bc18420a2429789d47bcb91eeb11cQuinoline and benzimidazole derivatives: Candidate probes for in vivo imaging of tau pathology in Alzheimer's diseaseOkamura, Nobuyuki; Suemoto, Takahiro; Furumoto, Shozo; Suzuki, Masako; Shimadzu, Hiroshi; Akatsu, Hiroyasu; Yamamoto, Takayuki; Fujiwara, Hironori; Nemoto, Miyako; Maruyama, Masahiro; Arai, Hiroyuki; Yanai, Kazuhiko; Sawada, Tohru; Kudo, YukitsukaJournal of Neuroscience (2005), 25 (47), 10857-10862CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Neurofibrillary tangles (NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathol. characteristics of Alzheimer's disease (AD). These lesions occur before the presentation of clin. symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclin. diagnosis of AD and for tracking disease progression. The present study introduces three novel compds., 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine (BF-126), 2-[(4-methylamino)phenyl]quinoline (BF-158), and 2-(4-aminophenyl)quinoline (BF-170), as candidate probes for in vivo imaging of tau pathol. in the AD brain. When solns. of these compds. are injected i.v. into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compds. display relatively lower binding affinity to β-amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathol. examn. using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiog. using 11C-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivs. for in vivo imaging of tau pathol. in AD.402Fodero-Tavoletti, M. T.; Okamura, N.; Furumoto, S.; Mulligan, R. S.; Connor, A. R.; McLean, C. A.; Cao, D.; Rigopoulos, A.; Cartwright, G. A.; O’Keefe, G.; Gong, S.; Adlard, P. A.; Barnham, K. J.; Rowe, C. C.; Masters, C. L.; Kudo, Y.; Cappai, R.; Yanai, K.; Villemagne, V. L. 18F-THK523: A novel in vivo tau imaging ligand for Alzheimer’s disease. Brain 2011, 134, 1089– 1100, DOI: 10.1093/brain/awr038[Crossref], [PubMed], [CAS], Google Scholar402https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MvgsVejsA%253D%253D&md5=4c6954ff8eed443bb6eaf040ffb88d3818F-THK523: a novel in vivo tau imaging ligand for Alzheimer's diseaseFodero-Tavoletti Michelle T; Okamura Nobuyuki; Furumoto Shozo; Mulligan Rachel S; Connor Andrea R; McLean Catriona A; Cao Diana; Rigopoulos Angela; Cartwright Glenn A; O'Keefe Graeme; Gong Sylvia; Adlard Paul A; Barnham Kevin J; Rowe Christopher C; Masters Colin L; Kudo Yukitsuka; Cappai Roberto; Yanai Kazuhiko; Villemagne Victor LBrain : a journal of neurology (2011), 134 (Pt 4), 1089-100 ISSN:.While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.403Villemagne, V. L.; Furumoto, S.; Fodero-Tavoletti, M. T.; Mulligan, R. S.; Hodges, J.; Kudo, Y.; Masters, C. L.; Yanai, K.; Rowe, C. C.; Okamura, N. In vivo tau imaging in Alzheimer’s disease. J. Nucl. Med. 2012, 53 (Suppl. 2), 111P404Shao, X.; Carpenter, G. M.; Desmond, T. J.; Sherman, P.; Quesada, C. A.; Fawaz, M.; Brooks, A. F.; Kilbourn, M. R.; Albin, R. L.; Frey, K. A.; Scott, P. J. H. Evaluation of [11C] N -methyl lansoprazole as a radiopharmaceutical for PET imaging of tau neurofibrillary tangles. ACS Med. Chem. Lett. 2012, 3, 936– 941, DOI: 10.1021/ml300216t[ACS Full Text], [CAS], Google Scholar404https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtl2lsr%252FI&md5=a1fd3561aca6b2d9366271582e9bf60fEvaluation of [11C]N-Methyl Lansoprazole as a Radiopharmaceutical for PET Imaging of Tau Neurofibrillary TanglesShao, Xia; Carpenter, Garrett M.; Desmond, Timothy J.; Sherman, Phillip; Quesada, Carole A.; Fawaz, Maria; Brooks, Allen F.; Kilbourn, Michael R.; Albin, Roger L.; Frey, Kirk A.; Scott, Peter J. H.ACS Medicinal Chemistry Letters (2012), 3 (11), 936-941CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)[11C]N-Me lansoprazole ([11C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomog. (PET) imaging. [11C]NML was synthesized from com. available lansoprazole in 4.6% radiochem. yield (noncorrected RCY, based upon [11C]MeI), 99% radiochem. purity, and 16095 Ci/mmol specific activity (n = 5). Log P was detd. to be 2.18. A lack of brain uptake in rodent microPET imaging revealed [11C]NML to be a substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by pretreating with cyclosporin A to block the PGP. Contrastingly, [11C]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [11C]NML uptake in the healthy primate brain of ∼1600 nCi/cc max. at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiog. between wild-type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [11C]NML in the cortex of brains expressing human tau. Further autoradiog. with tau pos. brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [11C]NML with tau NFTs identified using modified Bielschowsky staining. Finally, satn. binding expts. with heparin-induced tau confirmed Kd and Bmax values of [11C]NML as 700 pM and 0.214 fmol/μg, resp.405Gobbi, L. C.; Knust, H.; Körner, M.; Honer, M.; Czech, C.; Belli, S.; Muri, D.; Edelmann, M. R.; Hartung, T.; Erbsmehl, I.; Grall-Ulsemer, S.; Koblet, A.; Rueher, M.; Steiner, S.; Ravert, H. T.; Mathews, W. B.; Holt, D. P.; Kuwabara, H.; Valentine, H.; Dannals, R. F.; Wong, D. F.; Borroni, E. Identification of three novel radiotracers for imaging aggregated tau in Alzheimer’s disease with positron emission tomography. J. Med. Chem. 2017, 60, 7350– 7370, DOI: 10.1021/acs.jmedchem.7b00632[ACS Full Text], [CAS], Google Scholar405https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVOnsL7N&md5=599042bc3d648b54b2bad36aa6ec43baIdentification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission TomographyGobbi, Luca C.; Knust, Henner; Korner, Matthias; Honer, Michael; Czech, Christian; Belli, Sara; Muri, Dieter; Edelmann, Martin R.; Hartung, Thomas; Erbsmehl, Isabella; Grall-Ulsemer, Sandra; Koblet, Andreas; Rueher, Marianne; Steiner, Sandra; Ravert, Hayden T.; Mathews, William B.; Holt, Daniel P.; Kuwabara, Hiroto; Valentine, Heather; Dannals, Robert F.; Wong, Dean F.; Borroni, EdilioJournal of Medicinal Chemistry (2017), 60 (17), 7350-7370CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aggregates of tau and beta amyloid (Aβ) plaques constitute the histopathol. hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathol. forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aβ plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.406Turkheimer, F. E.; Rizzo, G.; Bloomfield, P. S.; Howes, O.; Zanotti-Fregonara, P.; Bertoldo, A.; Veronese, M. The methodology of TSPO imaging with positron emission tomography. Biochem. Soc. Trans. 2015, 43, 586– 592, DOI: 10.1042/BST20150058[Crossref], [PubMed], [CAS], Google Scholar406https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVCrsbzI&md5=e3086036c65c8ade42b65caa585e5e75The methodology of TSPO imaging with positron emission tomographyTurkheimer, Federico E.; Rizzo, Gaia; Bloomfield, Peter S.; Howes, Oliver; Zanotti-Fregonara, Paolo; Bertoldo, Alessandra; Veronese, MattiaBiochemical Society Transactions (2015), 43 (4), 586-592CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)A review. The 18-kDA translocator protein (TSPO) is consistently elevated in activated microglia of the central nervous system (CNS) in response to a variety of insults as well as neurodegenerative and psychiatric conditions. It is therefore a target of interest for mol. strategies aimed at imaging neuroinflammation in vivo. For more than 20 years, positron emission tomog. (PET) has allowed the imaging of TSPO d. in brain using [11C]-(R)-PK11195, a radiolabeled-specific antagonist of the TSPO that has demonstrated microglial activation in a large no. pathol. cohorts. The significant clin. interest in brain immunity as a primary or comorbid factor in illness has sparked great interest in the TSPO as a biomarker and a surprising no. of second generation TSPO radiotracers have been developed aimed at improving the quality of TSPO imaging through novel radioligands with higher affinity. However, such major investment has not yet resulted in the expected improvement in image quality. We here review the main methodol. aspects of TSPO PET imaging with particular attention to TSPO genetics, cellular heterogeneity of TSPO in brain tissue and TSPO distribution in blood and plasma that need to be considered in the quantification of PET data to avoid spurious results as well as ineffective development and use of these radiotracers.407Gershen, L. D.; Zanotti-Fregonara, P.; Dustin, I. H.; Liow, J.-S.; Hirvonen, J.; Kreisl, W. C.; Jenko, K. J.; Inati, S. K.; Fujita, M.; Morse, C. L.; Brouwer, C.; Hong, J. S.; Pike, V. W.; Zoghbi, S. S.; Innis, R. B.; Theodore, W. H. Neuroinflammation in temporal lobe epilepsy measured using positron emission tomographic imaging of translocator protein. JAMA Neurol. 2015, 72, 882, DOI: 10.1001/jamaneurol.2015.0941[Crossref], [PubMed], [CAS], Google Scholar407https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbhtFakuw%253D%253D&md5=cf61eb88e7a1a36486962814822ceb8dNeuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator ProteinGershen Leah D; Liow Jeih-San; Kreisl William C; Jenko Kimberly J; Fujita Masahiro; Morse Cheryl L; Brouwer Chad; Hong Jinsoo S; Pike Victor W; Zoghbi Sami S; Innis Robert B; Zanotti-Fregonara Paolo; Dustin Irene H; Inati Sara K; Theodore William H; Hirvonen JussiJAMA neurology (2015), 72 (8), 882-8 ISSN:.IMPORTANCE: Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([11C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES: To determine whether patients with TLE have widespread TSPO overexpression using [11C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [11C]PBR28 and another TSPO radioligand, [11C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS: In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [11C]PBR28, and 8 patients and 7 controls were scanned with [11C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURES: The [11C]PBR28 distribution volume (VT) corrected for free fraction (fP) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [11C]PBR28 and [11C]DPA-713 standardized uptake values from temporal regions. RESULTS: The [11C]PBR28 VT to fp ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%-42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%-32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [11C]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [11C]PBR28 was increased significantly in thalamus. Relative [11C]PBR28 and [11C]DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([11C]PBR28: 2%-6%; [11C]DPA-713: 4%-9%). Asymmetry of [11C]DPA-713 was greater than that of [11C]PBR28 (F = 29.4; P = .001). CONCLUSIONS AND RELEVANCE: Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug-resistant epilepsy.408Kreisl, W. C.; Lyoo, C. H.; McGwier, M.; Snow, J.; Jenko, K. J.; Kimura, N.; Corona, W.; Morse, C. L.; Zoghbi, S. S.; Pike, V. W.; McMahon, F. J.; Turner, R. S.; Innis, R. B. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain 2013, 136, 2228– 2238, DOI: 10.1093/brain/awt145[Crossref], [PubMed], [CAS], Google Scholar408https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sjjtlSgtA%253D%253D&md5=57cd580cdbeacbec216c5c5bcc1b5748In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's diseaseKreisl William C; Lyoo Chul Hyoung; McGwier Meghan; Snow Joseph; Jenko Kimberly J; Kimura Nobuyo; Corona Winston; Morse Cheryl L; Zoghbi Sami S; Pike Victor W; McMahon Francis J; Turner R Scott; Innis Robert BBrain : a journal of neurology (2013), 136 (Pt 7), 2228-38 ISSN:.Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.409Kreisl, W. C.; Fujita, M.; Fujimura, Y.; Kimura, N.; Jenko, K. J.; Kannan, P.; Hong, J.; Morse, C. L.; Zoghbi, S. S.; Gladding, R. L.; Jacobson, S.; Oh, U.; Pike, V. W.; Innis, R. B. Comparison of [11C]-(R)-PK 11195 and [11C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: Implications for positron emission tomographic imaging of this inflammation biomarker. NeuroImage 2010, 49, 2924– 2932, DOI: 10.1016/j.neuroimage.2009.11.056[Crossref], [PubMed], [CAS], Google Scholar409https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktlSkt7k%253D&md5=6ee406da710253d3b27ca9a494089f1eComparison of [11C]-(R)-PK 11195 and [11C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarkerKreisl, William C.; Fujita, Masahiro; Fujimura, Yota; Kimura, Nobuyo; Jenko, Kimberly J.; Kannan, Pavitra; Hong, Jinsoo; Morse, Cheryl L.; Zoghbi, Sami S.; Gladding, Robert L.; Jacobson, Steven; Oh, Unsong; Pike, Victor W.; Innis, Robert B.NeuroImage (2010), 49 (4), 2924-2932CODEN: NEIMEF; ISSN:1053-8119. (Elsevier B.V.)Ten percent of humans lack specific binding of [11C]PBR28 to 18 kDa translocator protein (TSPO), a biomarker for inflammation. "Non-binders" have not been reported using another TSPO radioligand, [11C]-(R)-PK 11195, despite its use for more than two decades. This study asked two questions: (1) What is the cause of non-binding to PBR28 and (2) Why has this phenomenon not been reported using [11C]-(R)-PK 11195. Methods: Five binders and five non-binders received whole-body imaging with both [11C]-(R)-PK 11195 and [11C]PBR28. In vitro binding was performed using leukocyte membranes from binders and non-binders and the tritiated versions of the ligand. Rhesus monkeys were imaged with [11C]-(R)-PK 11195 at baseline and after blockade of TSPOs. Results: Using [11C]PBR28, uptake in all five organs with high densities of TSPO (lung, heart, brain, kidney, and spleen) was 50% to 75% lower in non-binders than in binders. In contrast, [11C]-(R)-PK 11195 distinguished binders and non-binders in only heart and lung. For the in vitro assay, [3H]PBR28 had more than 10-fold lower affinity to TSPO in non-binders than in binders. The in vivo specific binding of [11C]-(R)-PK 11195 in monkey brain was ∼80-fold lower than that reported for [11C]PBR28. Conclusions: Based on binding of [3H] PK 11195 to leukocyte membranes, both binders and non-binders express TSPO. Non-binding to PBR28 is caused by its low affinity for TSPO in non-binders. Non-binding may be differentially expressed in organs of the body. The relatively low in vivo specific binding of [11C]-(R)-PK 11195 may have obscured its detection of non-binding in peripheral organs.410Kobayashi, M.; Jiang, T.; Telu, S.; Zoghbi, S. S.; Gunn, R. N.; Rabiner, E. A.; Owen, D. R.; Guo, Q.; Pike, V. W.; Innis, R. B.; Fujita, M. 11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195. J. Cereb. Blood Flow Metab. 2018, 38, 393– 403, DOI: 10.1177/0271678X17699223[Crossref], [PubMed], [CAS], Google Scholar410https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFOhtL0%253D&md5=d6bd9f42f469b96c3da8a7f79c77ad1311C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195Kobayashi, Masato; Jiang, Teresa; Telu, Sanjay; Zoghbi, Sami S.; Gunn, Roger N.; Rabiner, Eugenii A.; Owen, David R.; Guo, Qi; Pike, Victor W.; Innis, Robert B.; Fujita, MasahiroJournal of Cerebral Blood Flow & Metabolism (2018), 38 (3), 393-403CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)Positron emission tomog. (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent 11C-(R)-PK11195 in human imaging. This study sought to quant. measure the "signal to background" ratio (assessed as binding potential (BPND)) of 11C-(R)-PK11195 compared to one of the most promising second-generation radioligands, 11C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either 11C-(R)-PK11195 (16 subjects) or 11C-DPA-713 (22 subjects). To measure the amt. of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30-90 mg PO). 11C-DPA-713 showed a significant sensitivity to genotype in brain, whereas 11C-(R)-PK11195 did not. Lassen occupancy plot anal. revealed that the specific binding of 11C-DPA-713 was much greater than that of 11C-(R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for 11C-DPA-713 (7.3) than for 11C-(R)-PK11195 (0.75). Although the high specific binding of 11C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution vol. increased over time, consistent with the accumulation of radiometabolites in brain.411Cagnin, A.; Brooks, D. J.; Kennedy, A. M.; Gunn, R. N.; Myers, R.; Turkheimer, F. E.; Jones, T.; Banati, R. B. In-vivo measurement of activated microglia in dementia. Lancet 2001, 358, 461– 467, DOI: 10.1016/S0140-6736(01)05625-2[Crossref], [PubMed], [CAS], Google Scholar411https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MvmvVWjsw%253D%253D&md5=3574a5e3502039300c6f45a1403b57d7In-vivo measurement of activated microglia in dementiaCagnin A; Brooks D J; Kennedy A M; Gunn R N; Myers R; Turkheimer F E; Jones T; Banati R BLancet (London, England) (2001), 358 (9280), 461-7 ISSN:0140-6736.BACKGROUND: Activated microglia have a key role in the brain's immune response to neuronal degeneration. The transition of microglia from the normal resting state to the activated state is associated with an increased expression of receptors known as peripheral benzodiazepine binding sites, which are abundant on cells of mononuclear phagocyte lineage. We used brain imaging to study expression of these sites in healthy individuals and patients with Alzheimer's disease. METHODS: We studied 15 normal individuals (age 32-80 years), eight patients with Alzheimer's disease, and one patient with minimal cognitive impairment. Quantitative in-vivo measurements of glial activation were obtained with positron emission tomography (PET) and carbon-11-labelled (R)-PK11195, a specific ligand for the peripheral benzodiazepine binding site. FINDINGS: In normal individuals, regional [11C](R)-PK11195 binding did not significantly change with age, except in the thalamus, where an age-dependent increase was found. By contrast, patients with Alzheimer's disease showed significantly increased regional [11C](R)-PK11195 binding in the entorhinal, temporoparietal, and cingulate cortex. INTERPRETATION: In-vivo detection of increased [11C](R)-PK11195 binding in Alzheimer-type dementia, including mild and early forms, suggests that microglial activation is an early event in the pathogenesis of the disease.412Calsolaro, V.; Edison, P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimer's Dementia 2016, 12, 719– 732, DOI: 10.1016/j.jalz.2016.02.010[Crossref], [PubMed], [CAS], Google Scholar412https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28bpvVyhtg%253D%253D&md5=455f22ccbc7a16b20131d4d834935205Neuroinflammation in Alzheimer's disease: Current evidence and future directionsCalsolaro Valeria; Edison PaulAlzheimer's & dementia : the journal of the Alzheimer's Association (2016), 12 (6), 719-32 ISSN:.Several attempts have been made to treat Alzheimer's disease (AD) using anti-amyloid strategies with disappointing results. It is clear that the "amyloid cascade hypothesis" alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies. Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful. In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression. We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro-inflammatory factors, and neuronal damage. We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target.413Fan, Z.; Okello, A. A.; Brooks, D. J.; Edison, P. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease. Brain 2015, 138, 3685– 3698, DOI: 10.1093/brain/awv288[Crossref], [PubMed], [CAS], Google Scholar413https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zmsVSisQ%253D%253D&md5=42ef5ce0e01faabc925eaf1ed4b50673Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer's diseaseFan Zhen; Okello Aren A; Edison Paul; Brooks David JBrain : a journal of neurology (2015), 138 (Pt 12), 3685-98 ISSN:.Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer's disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer's disease. A group of eight patients with a diagnosis of Alzheimer's disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer's disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimer's disease process with associated synaptic dysfunction and reduced glucose metabolism. Voxel-wise correlation analysis suggests that neuroinflammation is associated with localized amyloid deposition and glucose metabolism over time, however, the level of inflammation could also occur independently of amyloid pathology, especially in the later stages of Alzheimer's disease.414Fan, Z.; Brooks, D. J.; Okello, A.; Edison, P. An early and late peak in microglial activation in Alzheimer’s disease trajectory. Brain 2017, 140, 792– 803, DOI: 10.1093/brain/aww349[Crossref], [PubMed], [CAS], Google Scholar414https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c7pt1yjsg%253D%253D&md5=42aba449a7fb9e714b63e0a9d952c1d5An early and late peak in microglial activation in Alzheimer's disease trajectoryFan Zhen; Brooks David J; Okello Aren; Edison Paul; Brooks David JBrain : a journal of neurology (2017), 140 (3), 792-803 ISSN:.Amyloid-β deposition, neuroinflammation and tau tangle formation all play a significant role in Alzheimer's disease. We hypothesized that there is microglial activation early on in Alzheimer's disease trajectory, where in the initial phase, microglia may be trying to repair the damage, while later on in the disease these microglia could be ineffective and produce proinflammatory cytokines leading to progressive neuronal damage. In this longitudinal study, we have evaluated the temporal profile of microglial activation and its relationship between fibrillar amyloid load at baseline and follow-up in subjects with mild cognitive impairment, and this was compared with subjects with Alzheimer's disease. Thirty subjects (eight mild cognitive impairment, eight Alzheimer's disease and 14 controls) aged between 54 and 77 years underwent 11C-(R)PK11195, 11C-PIB positron emission tomography and magnetic resonance imaging scans. Patients were followed-up after 14 ± 4 months. Region of interest and Statistical Parametric Mapping analysis were used to determine longitudinal alterations. Single subject analysis was performed to evaluate the individualized pathological changes over time. Correlations between levels of microglial activation and amyloid deposition at a voxel level were assessed using Biological Parametric Mapping. We demonstrated that both baseline and follow-up microglial activation in the mild cognitive impairment cohort compared to controls were increased by 41% and 21%, respectively. There was a longitudinal reduction of 18% in microglial activation in mild cognitive impairment cohort over 14 months, which was associated with a mild elevation in fibrillar amyloid load. Cortical clusters of microglial activation and amyloid deposition spatially overlapped in the subjects with mild cognitive impairment. Baseline microglial activation was increased by 36% in Alzheimer's disease subjects compared with controls. Longitudinally, Alzheimer's disease subjects showed an increase in microglial activation. In conclusion, this is one of the first longitudinal positron emission tomography studies evaluating longitudinal changes in microglial activation in mild cognitive impairment and Alzheimer's disease subjects. We found there is an initial longitudinal reduction in microglial activation in subjects with mild cognitive impairment, while subjects with Alzheimer's disease showed an increase in microglial activation. This could reflect that activated microglia in mild cognitive impairment initially may adopt a protective activation phenotype, which later change to a cidal pro-inflammatory phenotype as disease progresses and amyloid clearance fails. Thus, we speculate that there might be two peaks of microglial activation in the Alzheimer's disease trajectory; an early protective peak and a later pro-inflammatory peak. If so, anti-microglial agents targeting the pro-inflammatory phenotype would be most beneficial in the later stages of the disease.415Kreisl, W. C.; Lyoo, C. H.; Liow, J.-S.; Wei, M.; Snow, J.; Page, E.; Jenko, K. J.; Morse, C. L.; Zoghbi, S. S.; Pike, V. W.; Turner, R. S.; Innis, R. B. 11C-PBR28 binding to translocator protein increases with progression of Alzheimer’s disease. Neurobiol. Aging 2016, 44, 53– 61, DOI: 10.1016/j.neurobiolaging.2016.04.011[Crossref], [PubMed], [CAS], Google Scholar415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnslGmu7c%253D&md5=c7994f40cd6985e7253015ed5c6a9cae11C-PBR28 binding to translocator protein increases with progression of Alzheimer's diseaseKreisl, William C.; Lyoo, Chul Hyoung; Liow, Jeih-San; Wei, Monica; Snow, Joseph; Page, Emily; Jenko, Kimberly J.; Morse, Cheryl L.; Zoghbi, Sami S.; Pike, Victor W.; Turner, R. Scott; Innis, Robert B.Neurobiology of Aging (2016), 44 (), 53-61CODEN: NEAGDO; ISSN:0197-4580. (Elsevier)This longitudinal study sought to det. whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomog. imaging with the TSPO radioligand 11C-PBR28 was performed at baseline and after a median follow-up of 2.7 years in 14 amyloid-pos. patients and 8 amyloid-neg. controls. Patients had a greater increase in TSPO binding than controls in inferior parietal lobule, precuneus, occipital cortex, hippocampus, entorhinal cortex, and combined middle and inferior temporal cortex. TSPO binding in temporoparietal regions increased from 3.9% to 6.3% per annum in patients, but ranged from -0.5% to 1% per annum in controls. The change in TSPO binding correlated with cognitive worsening on clin. dementia rating scale-sum of boxes and reduced cortical vol. The annual rate of increased TSPO binding in temporoparietal regions was about 5-fold higher in patients with clin. progression (n = 9) compared with those who did not progress (n = 5). TSPO may serve as a biomarker of Alzheimer's progression and response to anti-inflammatory therapies.416Maeda, J.; Zhang, M.-R.; Okauchi, T.; Ji, B.; Ono, M.; Hattori, S.; Kumata, K.; Iwata, N.; Saido, T. C.; Trojanowski, J. Q.; Lee, V. M.-Y.; Staufenbiel, M.; Tomiyama, T.; Mori, H.; Fukumura, T.; Suhara, T.; Higuchi, M. In vivo positron emission tomographic imaging of glial responses to amyloid- and tau pathologies in mouse models of Alzheimer’s disease and related disorders. J. Neurosci. 2011, 31, 4720– 4730, DOI: 10.1523/JNEUROSCI.3076-10.2011[Crossref], [PubMed], [CAS], Google Scholar416https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVKrtbk%253D&md5=d3c03f77c86cb83aef2a8c46a0283713In vivo positron emission tomographic imaging of glial responses to amyloid-β and tau pathologies in mouse models of Alzheimer's disease and related disordersMaeda, Jun; Zhang, Ming-Rong; Okauchi, Takashi; Ji, Bin; Ono, Maiko; Hattori, Satoko; Kumata, Katsushi; Iwata, Nobuhisa; Saido, Takaomi C.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Staufenbiel, Matthias; Tomiyama, Takami; Mori, Hiroshi; Fukumura, Toshimitsu; Suhara, Tetsuya; Higuchi, MakotoJournal of Neuroscience (2011), 31 (12), 4720-4730CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-pos. microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-pos. tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomog. (PET) with 2 classes of TSPO radioligands, [11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was obsd. in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11C]Pittsburgh Compd.-B, to plaques. In these animals, [11C]AC-5216 yielded better TSPO contrasts than [18F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an addnl. line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. These data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.417Teodoro, R.; Moldovan, R.-P.; Lueg, C.; Günther, R.; Donat, C. K.; Ludwig, F.-A.; Fischer, S.; Deuther-Conrad, W.; Wünsch, B.; Brust, P. Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptors. Org. Med. Chem. Lett. 2013, 3, 11, DOI: 10.1186/2191-2858-3-11[Crossref], [PubMed], [CAS], Google Scholar417https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1Cqt7fM&md5=d04cb162a16c55d06d2639be02a8a282Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptorsTeodoro, Rodrigo; Moldovan, Rares-Petru; Lueg, Corinna; Guenther, Robert; Donat, Cornelius K.; Ludwig, Friedrich-Alexander; Fischer, Steffen; Deuther-Conrad, Winnie; Wuensch, Bernhard; Brust, PeterOrganic and Medicinal Chemistry Letters (2013), 3 (1), 11, 18 pp.CODEN: OMCLBC; ISSN:2191-2858. (Springer GmbH)Background: The level of expression of cannabinoid receptor type 2 (CB2R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB2R in the brain. Positron emission tomog. (PET) is an imaging technique, which allows quant. monitoring of very low amts. of radiolabeled compds. in living organisms at high temporal and spatial resoln. and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination of N-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biol. evaluation of the potential of the two tracers [18F]1 and [18F]2 as CB2 receptor PET imaging agents. Results: High binding affinity and specificity towards CB2 receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliph. and arom. fluorine in the selected labeling sites of 1 and 2. Aliph. and arom. radiofluorinations were optimized, and [18F]1 and [18F]2 were achieved in radiochem. yields of ≥30% with radiochem. purities of ≥98% and specific activities of 250 to 450 GBq/μmol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood-brain barrier (BBB) but undergo strong peripheral metab. At 30 min after injection, unmetabolized [18F]1 and [18F]2 accounted for 60% and 2% as well as 66% and 80% of the total activity in the plasma and brain, resp. The main radiometabolite of [18F]2 could be identified as the free acid [18F]10, which has no affinity towards the CB1 and CB2 receptors but can cross the BBB. Conclusions: N-aryl-oxadiazolyl-propionamides can successfully be radiolabeled with 18F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB2R. Despite a promising in vitro behavior, a rather rapid peripheral metab. of [18F]1 and [18F]2 in mice and the generation of brain permeable radiometabolites hamper the application of these radiotracers in vivo. However, it is expected that future synthetic modification aiming at a replacement of metabolically susceptible structural elements of [18F]1 and [18F]2 will help to elucidate the potential of this class of compds. for CB2R PET studies.418Zimmer, E.; Leuzy, A.; Benedet, A.; Breitner, J.; Gauthier, S.; Rosa-Neto, P. Tracking Neuroinflammation in Alzheimer’s Disease: The role of positron emission tomography imaging. J. Neuroinflammation 2014, 11, 120, DOI: 10.1186/1742-2094-11-120[Crossref], [PubMed], [CAS], Google Scholar418https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVCitrzJ&md5=99bc071c92e3e50cfdcee7860aa5179fTracking neuroinflammation in Alzheimer's disease: the role of positron emission tomography imagingZimmer, Eduardo Rigon; Leuzy, Antoine; Benedet, Andrea Lessa; Breitner, John; Gauthier, Serge; Rosa-Neto, PedroJournal of Neuroinflammation (2014), 11 (), 120/1-120/12CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)A review. Alzheimer's disease (AD) has been reconceptualized as a dynamic pathophysiol. process, where the accumulation of amyloid-beta (Aβ) is thought to trigger a cascade of neurodegenerative events resulting in cognitive impairment and, eventually, dementia. In addn. to Aβ pathol., various lines of research have implicated neuroinflammation as an important participant in AD pathophysiol. Currently, neuroinflammation can be measured in vivo using positron emission tomog. (PET) with ligands targeting diverse biol. processes such as microglial activation, reactive astrocytes and phospholipase A2 activity. In terms of therapeutic strategies, despite a strong rationale and epidemiol. studies suggesting that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the prevalence of AD, clin. trials conducted to date have proven inconclusive. In this respect, it has been hypothesized that NSAIDs may only prove protective if administered early on in the disease course, prior to the accumulation of significant AD pathol. In order to test various hypotheses pertaining to the exact role of neuroinflammation in AD, studies in asymptomatic carriers of mutations deterministic for early-onset familial AD may prove of use. In this respect, PET ligands for neuroinflammation may act as surrogate markers of disease progression, allowing for the development of more integrative models of AD, as well as for the measuring of target engagement in the context of clin. trials using NSAIDs. In this review, we address the biol. basis of neuroinflammatory changes in AD, underscore therapeutic strategies using anti-inflammatory compds., and shed light on the possibility of tracking neuroinflammation in vivo using PET imaging ligands.419Moldovan, R.-P.; Hausmann, K.; Deuther-Conrad, W.; Brust, P. Development of highly affine and selective fluorinated cannabinoid type 2 receptor ligands. ACS Med. Chem. Lett. 2017, 8, 566– 571, DOI: 10.1021/acsmedchemlett.7b00129[ACS Full Text], [CAS], Google Scholar419https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmslKrtrw%253D&md5=1c8da7e06fb35ae367e71a94fa08f49cDevelopment of Highly Affine and Selective Fluorinated Cannabinoid Type 2 Receptor LigandsMoldovan, Rares-Petru; Hausmann, Kristin; Deuther-Conrad, Winnie; Brust, PeterACS Medicinal Chemistry Letters (2017), 8 (5), 566-571CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Cannabinoid type 2 receptors (CB2 receptors) are involved in various pathol. processes, and the visualization of their in vivo availability with positron emission tomog. (PET) is of high interest. The study focuses on the introduction of fluorine into the structure of the highly affine and selective CB2 receptor ligand N-(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (5). A novel series of compds. was developed by modifying (i) the adamantane-3-position, (ii) the imidazole-N-Ph ring, and (iii) the imidazole-2-position, and the impact on the CB2 binding affinity and selectivity toward cannabinoid type 1 receptors (CB1) was evaluated. This study identified compd. 15 as one of the most potent (Ki(CB2) = 0.29 nM) and selective (CB1/CB2 > 10000) CB2 receptor ligands discovered so far, eligible for the development of an 18F-labeled PET radiotracer.420Chen, M.-K.; Guilarte, T. R. Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair. Pharmacol. Ther. 2008, 118, 1– 17, DOI: 10.1016/j.pharmthera.2007.12.004[Crossref], [PubMed], [CAS], Google Scholar420https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlvVSqsb0%253D&md5=19a49bb0a99b1b167bdd8b63ca61c5d2Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repairChen, Ming-Kai; Guilarte, Tomas R.Pharmacology & Therapeutics (2008), 118 (1), 1-17CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review. For over 15 years, the peripheral benzodiazepine receptor (PBR), recently named translocator protein 18 kDa (TSPO) has been studied as a biomarker of reactive gliosis and inflammation assocd. with a variety of neuropathol. conditions. Early studies documented that in the brain parenchyma, TSPO is exclusively localized in glial cells. Under normal physiol. conditions, TSPO levels are low in the brain neuropil but they markedly increase at sites of brain injury and inflammation making it uniquely suited for assessing active gliosis. This research has generated significant efforts from multiple research groups throughout the world to apply TSPO as a marker of "active" brain pathol. using in vivo imaging modalities such as Positron Emission Tomog. (PET) in exptl. animals and humans. Further, in the last few years, there has been an increased interest in understanding the mol. and cellular function(s) of TSPO in glial cells. The latest evidence suggests that TSPO may not only serve as a biomarker of active brain disease but also the use of TSPO-specific ligands may have therapeutic implications in brain injury and repair. This review presents an overview of the history and function of TSPO focusing on studies related to its use as a sensor of active brain disease in exptl. animals and in human studies.421Hirvonen, J.; Kreisl, W. C.; Fujita, M.; Dustin, I.; Khan, O.; Appel, S.; Zhang, Y.; Morse, C.; Pike, V. W.; Innis, R. B.; Theodore, W. H. Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy. J. Nucl. Med. 2012, 53, 234– 240, DOI: 10.2967/jnumed.111.091694[Crossref], [PubMed], [CAS], Google Scholar421https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjsVSltLo%253D&md5=ef475e7c8d24ea63d83345fabdc5b120Increased in vivo expression of an inflammatory marker in temporal lobe epilepsyHirvonen, Jussi; Kreisl, William C.; Fujita, Masahiro; Dustin, Irene; Khan, Omar; Appel, Shmuel; Zhang, Yi; Morse, Cheryl; Pike, Victor W.; Innis, Robert B.; Theodore, William H.Journal of Nuclear Medicine (2012), 53 (2), 234-240CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Animal studies and clin. observations suggest that epilepsy is assocd. with inflammation. Translocator protein (TSPO) (18 kDa), a marker of inflammation, is increased in vitro in surgical samples from patients with temporal lobe epilepsy. TSPO can be measured in the living human brain with PET and the novel radioligand 11C-PBR28. In this study, we sought to det. whether in vivo expression of TSPO is increased ipsilateral to the seizure focus in patients with temporal lobe epilepsy. Methods: Sixteen patients with unilateral temporal lobe epilepsy and 30 healthy subjects were studied with 11C-PBR28 PET and MRI. Uptake of radioactivity after injection of 11C-PBR28 was measured from regions of interest drawn bilaterally onto MR images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired-samples t test. Results: We found that brain uptake was higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without. Conclusion: We found increased uptake of radioactivity after injection of 11C-PBR28 ipsilateral to the seizure focus in patients with temporal lobe epilepsy, suggesting increased expression of TSPO. Studies in larger samples are required to confirm this finding and det. the clin. utility of imaging TSPO in temporal lobe epilepsy.422Boutin, H.; Chauveau, F.; Thominiaux, C.; Gregoire, M.-C.; James, M. L.; Trebossen, R.; Hantraye, P.; Dolle, F.; Tavitian, B.; Kassiou, M. 11C-DPA-713: A novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J. Nucl. Med. 2007, 48, 573– 581, DOI: 10.2967/jnumed.106.036764[Crossref], [PubMed], [CAS], Google Scholar422https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVert7nK&md5=55c934a5f699ff8890ecb90481b09a9211C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammationBoutin, Herve; Chauveau, Fabien; Thominiaux, Cyrille; Gregoire, Marie-Claude; James, Michelle L.; Trebossen, Regine; Hantraye, Philippe; Dolle, Frederic; Tavitian, Bertrand; Kassiou, MichaelJournal of Nuclear Medicine (2007), 48 (4), 573-581CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)The induction of neuroinflammatory processes, characterized by upregulation of the peripheral benzodiazepine receptor (PBR) expressed by microglial cells, is well correlated with neurodegenerative diseases and with acute neuronal loss. The continually increasing incidence of neurodegenerative diseases in developed countries has become a major health problem, for which the development of diagnostic and follow-up tools is required. Here we investigated a new PBR ligand suitable for PET to monitor neuroinflammatory processes as an indirect hallmark of neurodegeneration. We compared PK11195, the ref. compd. for PBR binding sites, with the new ligand DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), a PET scan was performed using 11C-PK11195 or 11C-DPA-713. Immunohistochem. for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD11) specific markers as well as 3H-PK11195 autoradiog. studies were then correlated with the imaging data. Seven days after a unilateral injection of AMPA in the striatum, 11C-DPA-713 exhibits a better contrast between healthy and damaged brain parenchyma than 11C-PK11195 (2.5-fold ± 0.14 increase vs. 1.6-fold ± 0.05 increase, resp.). 11C-DPA-713 and 11C-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, 11C-DPA-713 uptake was significantly lower than 11C-PK11195. Modeling of the data using the simplified ref. tissue model shows that the binding potential was significantly higher for 11C-DPA-713 than for 11C-PK11195. 11C-DPA-713 displays a higher signal-to-noise ratio than 11C-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of 11C-DPA-713. Although further studies in humans are required, 11C-DPA-713 represents a suitable alternative to 11C-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.423Chaney, A. M.; Johnson, E. M.; Cropper, H. C.; James, M. L. PET imaging of neuroinflammation using [11C]DPA-713 in a mouse model of ischemic stroke. J. Visualized Exp. 2018, 136, 57243, DOI: 10.3791/57243424Butler, T.; Ichise, M.; Teich, A. F.; Gerard, E.; Osborne, J.; French, J.; Devinsky, O.; Kuzniecky, R.; Gilliam, F.; Pervez, F.; Provenzano, F.; Goldsmith, S.; Vallabhajosula, S.; Stern, E.; Silbersweig, D. Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. Journal of Neuroimaging. 2013, 23, 129– 131, DOI: 10.1111/j.1552-6569.2010.00572.x[Crossref], [PubMed], [CAS], Google Scholar424https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38zjsFSltA%253D%253D&md5=da9523048f08c0c471976b158b6d1514Imaging inflammation in a patient with epilepsy due to focal cortical dysplasiaButler Tracy; Ichise Masanori; Teich Andrew F; Gerard Elizabeth; Osborne Joseph; French Jacqueline; Devinsky Orrin; Kuzniecky Ruben; Gilliam Frank; Pervez Fahad; Provenzano Frank; Goldsmith Stanley; Vallabhajosula Shankar; Stern Emily; Silbersweig DavidJournal of neuroimaging : official journal of the American Society of Neuroimaging (2013), 23 (1), 129-31 ISSN:.BACKGROUND AND PURPOSE: Evidence from animal models and examination of human epilepsy surgery specimens indicates that inflammation plays an important role in epilepsy. Positron emission tomography (PET) using [C11]PK11195, a marker of activated microglia, provides a means to visualize neuroinflammation in vivo in humans. We hypothesize that in patients with active epilepsy, [C11]PK11195 PET (PK-PET) may be able to identify areas of focally increased inflammation corresponding to the seizure onset zone. METHODS: A young woman with intractable epilepsy underwent PK-PET as part of an approved research study. PK-PET results were compared with results from other clinical studies. RESULTS: PK-PET revealed an area of focally increased radiotracer uptake in the right frontal lobe corresponding to this patient's seizure focus as identified by ictal and interictal 18F-fluorodeoxyglucose (FDG)-PET and EEG. Routine brain magnetic resonance imaging (MRI) was initially considered normal, though high-resolution studies showed possible subtle dysplasia of the right frontal lobe. The patient underwent a right frontal lobe resection, and pathological evaluation showed focal cortical dysplasia with activated microglia. CONCLUSIONS: PK-PET can identify neuroinflammation associated with subtle focal cortical dysplasia, and may therefore have a clinical role in guiding epilepsy surgery for patients with difficult-to-localize seizure foci.425Banati, R. B.; Goerres, G. W.; Myers, R.; Gunn, R. N.; Turkheimer, F. E.; Kreutzberg, G. W.; Brooks, D. J.; Jones, T.; Duncan, J. S. [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis. Neurology 1999, 53, 2199– 2199, DOI: 10.1212/WNL.53.9.2199[Crossref], [PubMed], [CAS], Google Scholar425https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c%252Fms1OqsA%253D%253D&md5=94ef58d64e1233fbd601561731b5529b11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitisBanati R B; Goerres G W; Myers R; Gunn R N; Turkheimer F E; Kreutzberg G W; Brooks D J; Jones T; Duncan J SNeurology (1999), 53 (9), 2199-203 ISSN:0028-3878.This study was designed to explore the feasibility of PET using [11C](R)-PK11195 as an in vivo marker of activated microglia/brain macrophages for the assessment of neuroinflammation in Rasmussen's encephalitis (RE). [11C](R)-PK11195 PET was carried out in four normal subjects, two patients with histologically confirmed RE, and three patients with clinically stable hippocampal sclerosis and low seizure frequency. Binding potential maps showing specific binding of [11C](R)-PK11195 were generated for each subject. Regional binding potential values were calculated for anatomically defined regions of interest after coregistration to and spatial transformation into the subjects' own MRI. In one patient with RE who underwent hemispherectomy, the resected, paraffin-embedded brain tissue was stained with an antibody (CR3/43) that labels activated human microglia. Whereas specific binding of [11C](R)-PK11195 in clinically stable hippocampal sclerosis was similar to that in normal brain, patients with RE showed a focal and diffuse increase in binding throughout the affected hemisphere. In RE, [11C](R)-PK11195 PET can reveal in vivo the characteristic, unilateral pattern known from postmortem neuropathologic study. PET imaging of activated microglia/brain macrophages offers a tool for investigation of a range of brain diseases where neuroinflammation is a component and in which conventional MRI does not unequivocally indicate an inflammatory tissue reaction. [11C](R)-PK11195 PET may help in the choice of appropriate biopsy sites and, further, may allow assessment of the efficacy of antiinflammatory disease-modifying treatment.426Gerhard, A.; Trender-Gerhard, I.; Turkheimer, F.; Quinn, N. P.; Bhatia, K. P.; Brooks, D. J. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov. Disord. 2006, 21, 89– 93, DOI: 10.1002/mds.20668[Crossref], [PubMed], [CAS], Google Scholar426https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28%252FjtlOkug%253D%253D&md5=43a010a5833feacfb848bbc8690b48ffIn vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsyGerhard Alexander; Trender-Gerhard Iris; Turkheimer Federico; Quinn Niall P; Bhatia Kailash P; Brooks David JMovement disorders : official journal of the Movement Disorder Society (2006), 21 (1), 89-93 ISSN:0885-3185.Progressive supranuclear palsy (PSP) is a neurodegenerative disease presenting with voluntary gaze difficulties, early falls, and Parkinsonism. Neuronal loss, associated with intracellular neurofibrillary tangles and activated microglia, is found targeting the basal ganglia, brainstem nuclei, and frontal cortex. [11C](R)-PK11195 PET is a marker of peripheral benzodiazepine binding sites (PBBS) expressed by activated microglia. We have used [11C](R)-PK11195 PET to demonstrate in vivo the degree and distribution of the glial response to the degenerative process in four patients with PSP. Compared to normal age-matched controls, the PSP patient group showed significantly increased mean [11C](R)-PK11195 binding in the basal ganglia, midbrain, the frontal lobe, and the cerebellum. Two of the patients were rescanned after 6 to 10 months and during that time the level of microglial activation remained stable. [11C](R)-PK11195 PET reveals a pattern of increased microglial activation in PSP patients involving cortical and subcortical regions that corresponds well with the known distribution of neuropathological changes. [11C](R)-PK11195 PET, therefore, may help in characterizing in vivo the underlying disease activity in PSP.427Passamonti, L.; Rodríguez, P. V.; Hong, Y. T.; Allinson, K. S. J.; Bevan-Jones, W. R.; Williamson, D.; Jones, P. S.; Arnold, R.; Borchert, R. J.; Surendranathan, A.; Mak, E.; Su, L.; Fryer, T. D.; Aigbirhio, F. I.; O’Brien, J. T.; Rowe, J. B. [11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy. Neurology 2018, 90, e1989 DOI: 10.1212/WNL.0000000000005610[Crossref], [PubMed], [CAS], Google Scholar427https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVags7zO&md5=b03709a8cfd65805b105bfb6921ff103[11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsyPassamonti, Luca; Rodriguez, Patricia Vazquez; Hong, Young T.; Allinson, Kieren S. J.; Bevan-Jones, W. Richard; Williamson, David; Jones, P. Simon; Arnold, Robert; Borchert, Robin J.; Surendranathan, Ajenthan; Mak, Elijah; Su, Li; Fryer, Tim D.; Aigbirhio, Franklin I.; O'Brien, John T.; Rowe, James B.Neurology (2018), 90 (22), e1989-e1996CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: We tested whether in vivo neuroinflammation relates to the distinctive distributions of pathol. in Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Methods: Sixteen patients with symptomatic AD (including amnestic mild cognitive impairment with amyloid-pos. PET scan), 16 patients with PSP-Richardson syndrome, and 13 age-, sex-, and education-matched healthy controls were included in this case-control study. Participants underwent [C]PK11195 PET scanning, which was used as an in vivo index of neuroinflammation. Results: [C]PK11195 binding in the medial temporal lobe and occipital, temporal, and parietal cortices was increased in patients with AD, relative both to patients with PSP and to controls. Compared to controls, patients with PSP showed elevated [C]PK11195 binding in the thalamus, putamen, and pallidum. [C]PK11195 binding in the cuneus/precuneus correlated with episodic memory impairment in AD, while [C]PK11195 binding in the pallidum, midbrain, and pons correlated with disease severity in PSP. Conclusions: Together, our results suggest that neuroinflammation has an important pathogenic role in the 2 very different human neurodegenerative disorders of AD and PSP. The increase and distribution of microglial activation suggest that immunotherapeutic strategies may be useful in slowing the progression of both diseases.428Cagnin, A.; Rossor, M.; Sampson, E. L.; MacKinnon, T.; Banati, R. B. In vivo detection of microglial activation in frontotemporal dementia. Ann. Neurol. 2004, 56, 894– 897, DOI: 10.1002/ana.20332[Crossref], [PubMed], [CAS], Google Scholar428https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2crpsFKmtA%253D%253D&md5=8794eeac45992a918676d776faa582c1In vivo detection of microglial activation in frontotemporal dementiaCagnin Annachiara; Rossor Martin; Sampson Elizabeth L; Mackinnon Toby; Banati Richard BAnnals of neurology (2004), 56 (6), 894-7 ISSN:0364-5134.Using positron emission tomography and [(11)C](R)-PK11195, a marker of "peripheral benzodiazepine sites" that is upregulated on activated microglia during progressive tissue pathology, we show increased binding of [(11)C](R)-PK11195 in frontotemporal lobar degeneration in the typically affected frontotemporal brain regions. This implies the presence of an active glial response reflecting progressive neuronal degeneration. It also suggests that increased [(11)C](R)-PK11195 binding, previously demonstrated for Alzheimer's disease, may occur independently from increased amyloid plaque formation, given that it is not a characteristic feature of frontotemporal lobar degeneration.429Kim, M.-J.; McGwier, M.; Jenko, K. J.; Snow, J.; Morse, C.; Zoghbi, S. S.; Pike, V. W.; Innis, R. B.; Kreisl, W. C. Neuroinflammation in frontotemporal lobar degeneration revealed by 11C-PBR28 PET. Ann. Clin. Transl. Neurol. 2019, 6, 1327– 1331, DOI: 10.1002/acn3.50802[Crossref], [PubMed], [CAS], Google Scholar429https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVertr3J&md5=119fc55f76058b39b14657ca9dc154c4Neuroinflammation in frontotemporal lobar degeneration revealed by 11C-PBR28 PETKim, Min-Jeong; McGwier, Meghan; Jenko, Kimberly J.; Snow, Joseph; Morse, Cheryl; Zoghbi, Sami S.; Pike, Victor W.; Innis, Robert B.; Kreisl, William C.Annals of Clinical and Translational Neurology (2019), 6 (7), 1327-1331CODEN: ACTNCG; ISSN:2328-9503. (John Wiley & Sons, Inc.)This study used 11C-PBR28 positron emission tomog. (PET) imaging to det. whether levels of 18-kDa translocator protein (TSPO), an inflammation-specific biomarker, are increased in frontotemporal lobar degeneration (FTLD) patients. 11C-PBR28, 18F-FDG, and 11C-PIB brain PET scans, as well as magnetic resonance imaging (MRI), were conducted in four FTLD patients and 22 healthy controls. 11C-PBR28 scans revealed that all FTLD patients showed increased TSPO binding vs. controls. Significantly greater increases in TSPO were obsd. in the frontal, lateral temporal, parietal, and occipital cortices, topog. consistent with individual clin. phenotypes and with brain MRI and 18F-FDG PET. Amyloid burden was not increased.430Hammoud, D. A.; Endres, C. J.; Chander, A. R.; Guilarte, T. R.; Wong, D. F.; Sacktor, N. C.; McArthur, J. C.; Pomper, M. G. Imaging glial cell activation with [11C]- R -PK11195 in patients with AIDS. J. NeuroVirol. 2005, 11, 346– 355, DOI: 10.1080/13550280500187351[Crossref], [PubMed], [CAS], Google Scholar430https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVWitLjJ&md5=476b5e302b64e4bebae9797146d5c883Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDSHammoud, Dima A.; Endres, Christopher J.; Chander, Ankit R.; Guilarte, Tomas R.; Wong, Dean F.; Sacktor, Ned C.; McArthur, Justin C.; Pomper, Martin G.Journal of NeuroVirology (2005), 11 (4), 346-355CODEN: JNVIFK; ISSN:1355-0284. (Taylor & Francis, Inc.)Glial cell activation occurs in response to brain injury and is present in a wide variety of inflammatory processes including dementia assocd. with human immunodeficiency virus (HIV). HIV-infected glial cells release cytokines and chemokines that, along with viral neurotoxins, contribute to neuronal damage and apoptosis. The purpose of this study was to det. if glial cell activation in HIV-pos. (HIV+) patients could be detected noninvasively, in vivo, using [11C]-R-PK11195 with positron emission tomog. (PET). [11C]-R-PK11195 is a selective radioligand for the peripheral benzodiazepine receptor (PBR), and is known to reflect the extent of glial cell activation. A subaim was to det. if nondemented HIV+ patients could be distinguished from those with HIV-assocd. dementia (HAD) on the basis of [11C]-R-PK11195 binding. Five healthy volunteers and 10 HIV+ patients underwent PET with [11C]-R-PK11195. Time-radioactivity curves (TACs) were generated from dynamic PET images in nine regions of interest (ROIs) drawn on coregistered magnetic resonance imaging (MRI) scans. The av. radioactivity was calcd. in each ROI and was normalized to the av. radioactivity in white matter. Patients with HAD showed significantly higher [11C]-R-PK11195 binding than controls in five out of eight brain regions. Nondemented HIV+ patients did not show significantly increased binding compared to controls. HIV+ patients overall (demented and nondemented) showed significantly higher radioligand binding than controls in five brain regions. Patients with HAD did not show significant differences in binding when compared to HIV+ nondemented patients. The findings of this pilot study support a role for glial cell activation in HAD, and that PET with [11C]-R-PK11195 can detect the concomitants of neuronal damage in individuals infected with HIV.431Coughlin, J. M.; Wang, Y.; Ma, S.; Yue, C.; Kim, P. K.; Adams, A. V.; Roosa, H. V.; Gage, K. L.; Stathis, M.; Rais, R.; Rojas, C.; McGlothan, J. L.; Watkins, C. C.; Sacktor, N.; Guilarte, T. R.; Zhou, Y.; Sawa, A.; Slusher, B. S.; Caffo, B.; Kassiou, M.; Endres, C. J.; Pomper, M. G. Regional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIV. J. NeuroVirol. 2014, 20, 219– 232, DOI: 10.1007/s13365-014-0239-5[Crossref], [PubMed], [CAS], Google Scholar431https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptVCksr4%253D&md5=3434731fbfcd7d4335294395be863daaRegional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIVCoughlin, Jennifer M.; Wang, Yuchuan; Ma, Shuangchao; Yue, Chen; Kim, Pearl K.; Adams, Ashley V.; Roosa, Heidi V.; Gage, Kenneth L.; Stathis, Marigo; Rais, Rana; Rojas, Camilo; McGlothan, Jennifer L.; Watkins, Crystal C.; Sacktor, Ned; Guilarte, Tomas R.; Zhou, Yun; Sawa, Akira; Slusher, Barbara S.; Caffo, Brian; Kassiou, Michael; Endres, Christopher J.; Pomper, Martin G.Journal of NeuroVirology (2014), 20 (3), 219-232CODEN: JNVIFK; ISSN:1355-0284. (Springer)Imaging the brain distribution of translocator protein (TSPO), a putative biomarker for glial cell activation and neuroinflammation, may inform management of individuals infected with HIV by uncovering regional abnormalities related to neurocognitive deficits and enable non-invasive therapeutic monitoring. Using the second-generation TSPO-targeted radiotracer, [11C]DPA-713, we conducted a positron emission tomog. (PET) study to compare the brains of 12 healthy human subjects to those of 23 individuals with HIV who were effectively treated with combination antiretroviral therapy (cART). Compared to PET data from age-matched healthy control subjects, [11C]DPA-713 PET of individuals infected with HIV demonstrated significantly higher vol.-of-distribution (VT) ratios in white matter, cingulate cortex, and supramarginal gyrus, relative to overall gray matter VT, suggesting localized glial cell activation in susceptible regions. Regional TSPO abnormalities were evident within a sub-cohort of neuro-asymptomatic HIV subjects, and an increase in the VT ratio within frontal cortex was specifically linked to individuals affected with HIV-assocd. dementia. These findings were enabled by employing a gray matter normalization approach for PET data quantification, which improved test-retest reproducibility, intra-class correlation within the healthy control cohort, and sensitivity of uncovering abnormal regional findings.432Vera, J. H.; Guo, Q.; Cole, J. H.; Boasso, A.; Greathead, L.; Kelleher, P.; Rabiner, E. A.; Kalk, N.; Bishop, C.; Gunn, R. N.; Matthews, P. M.; Winston, A. Neuroinflammation in treated HIV-positive individuals: A TSPO PET study. Neurology 2016, 86, 1425– 1432, DOI: 10.1212/WNL.0000000000002485[Crossref], [PubMed], [CAS], Google Scholar432https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xmt1aqsLw%253D&md5=e86a6b61cceffee711e1ed1e808afdb4Neuroinflammation in treated HIV-positive individuals: A TSPO PET studyVera, Jaime H.; Guo, Qi; Cole, James H.; Boasso, Adriano; Greathead, Louise; Kelleher, Peter; Rabiner, Eugenii A.; Kalk, Nicola; Bishop, Courtney; Gunn, Roger N.; Matthews, Paul M.; Winston, AlanNeurology (2016), 86 (15), 1425-1432CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: To explore the effects of microglial activation on brain function and structure, and its relationship with peripheral inflammatory markers, in treated, HIV-pos. individuals, using in vivo [C]PBR28 PET (to measure the 18 kDa translocator protein [TSPO]). Methods: Cognitively healthy HIV-pos. individuals on suppressive antiretroviral therapy and HIV-neg. individuals (controls) underwent brain [C]PBR28 PET and MRI. HIV-pos. patients completed neuropsychol. testing and CSF testing for chemokines. The concn. of bacterial ribosomal 16sDNA in plasma was measured as a marker of microbial translocation. Results: HIV-pos. individuals showed global increases in TSPO expression compared to controls (cor. p < 0.01), with significant regional increases in the parietal (p = 0.001) and occipital (p = 0.046) lobes and in the globus pallidus (p = 0.035). TSPO binding in the hippocampus, amygdala, and thalamus were assocd. with poorer global cognitive performance in tasks assessing verbal and visual memory (p < 0.05). Increased TSPO binding was assocd. with increased brain white matter diffusion MRI mean diffusivity in HIV-pos. individuals, a lower CD4/CD8 ratio, and both high pretreatment HIV RNA and plasma concn. ribosomal 16s DNA (p < 0.05). Conclusions: Cognitively healthy HIV-pos. individuals show evidence for a chronically activated brain innate immune response and elevated blood markers of microbial translocation despite effective control of plasma viremia. Increased brain inflammation is assocd. with poorer cognitive performance and white matter microstructural pathol., suggesting a possible role in cognitive impairments found in some HIV-pos. patients despite effective treatment.433Kreisl, W. C.; Mbeo, G.; Fujita, M.; Zoghbi, S. S.; Pike, V. W.; Innis, R. B.; McArthur, J. C. Stroke incidentally identified using improved positron emission tomography for microglial activation. Arch. Neurol. 2009, 66, 1288– 1289, DOI: 10.1001/archneurol.2009.208[Crossref], [PubMed], [CAS], Google Scholar433https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnosF2mtg%253D%253D&md5=316336ae3ec1963c083f61a7054c25ceStroke incidentally identified using improved positron emission tomography for microglial activationKreisl William C; Mbeo Gilbert; Fujita Masahiro; Zoghbi Sami S; Pike Victor W; Innis Robert B; McArthur Justin CArchives of neurology (2009), 66 (10), 1288-9 ISSN:.There is no expanded citation for this reference.434Abid, K. A.; Sobowale, O. A.; Parkes, L. M.; Naish, J.; Parker, G. J. M.; du Plessis, D.; Brough, D.; Barrington, J.; Allan, S. M.; Hinz, R.; Parry-Jones, A. R. Assessing inflammation in acute intracerebral hemorrhage with PK11195 PET and dynamic contrast-enhanced MRI. J. Neuroimaging. 2018, 28, 158– 161, DOI: 10.1111/jon.12477[Crossref], [PubMed], [CAS], Google Scholar434https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7jvFSntQ%253D%253D&md5=337b65a99958337c01ab5e8741d6d015Assessing Inflammation in Acute Intracerebral Hemorrhage with PK11195 PET and Dynamic Contrast-Enhanced MRIAbid Kamran A; Sobowale Oluwaseun A; Parkes Laura M; Naish Josephine; Parker Geoff J M; Brough David; Barrington Jack; Allan Stuart M; Hinz Rainer; Parry-Jones Adrian R; Abid Kamran A; Sobowale Oluwaseun A; du Plessis Daniel; Parry-Jones Adrian R; Parker Geoff J MJournal of neuroimaging : official journal of the American Society of Neuroimaging (2018), 28 (2), 158-161 ISSN:.BACKGROUND AND PURPOSE: Studies in animal models suggest that inflammation is a major contributor to secondary injury after intracerebral hemorrhage (ICH). Direct, noninvasive monitoring of inflammation in the human brain after ICH will facilitate early-phase development of anti-inflammatory treatments. We sought to investigate the feasibility of multimodality brain imaging in subacute ICH. METHODS: Acute ICH patients were recruited to undergo multiparametric MRI (including dynamic contrast-enhanced measurement of blood-brain barrier transfer constant (K(trans) ) and PET with [(11) C]-(R)-PK11195). [(11) C]-(R)-PK11195 binds to the translocator protein 18 kDa (TSPO), which is rapidly upregulated in activated microglia. Circulating inflammatory markers were measured at the time of PET. RESULTS: Five patients were recruited to this feasibility study with imaging between 5 and 16 days after onset. Etiologies included hypertension-related small vessel disease, cerebral amyloid angiopathy (CAA), cavernoma, and arteriovenous malformation (AVM). [(11) C]-(R)-PK11195 binding was low in all hematomas and 2 (patient 2 [probable CAA] and 4 [AVM]) cases showed widespread increase in binding in the perihematomal region versus contralateral. All had increased K(trans) in the perihematomal region (mean difference = 2.2 × 10(-3) minute(-1) ; SD = 1.6 × 10(-3) minute(-1) ) versus contralateral. Two cases (patients 1 [cavernoma] and 4 [AVM]) had delayed surgery (3 and 12 months post-onset, respectively) with biopsies showing intense microglial activation in perilesional tissue. CONCLUSIONS: Our study demonstrates for the first time the feasibility of performing complex multimodality brain imaging for noninvasive monitoring of neuroinflammation for this severe stroke subtype.435Turner, M. R.; Cagnin, A.; Turkheimer, F. E.; Miller, C. C. J.; Shaw, C. E.; Brooks, D. J.; Leigh, P. N.; Banati, R. B. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: An [11C](R)-PK11195 positron emission tomography study. Neurobiol. Dis. 2004, 15, 601– 609, DOI: 10.1016/j.nbd.2003.12.012[Crossref], [PubMed], [CAS], Google Scholar435https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXivVKmsro%253D&md5=a30edf14a0c20ea64c78dc1330785aceEvidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography studyTurner, M. R.; Cagnin, A.; Turkheimer, F. E.; Miller, C. C. J.; Shaw, C. E.; Brooks, D. J.; Leigh, P. N.; Banati, R. B.Neurobiology of Disease (2004), 15 (3), 601-609CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Science)Microglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the "peripheral benzodiazepine binding site" expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [11C](R)-PK11195 PET of the brain. Vols. of interest were defined to obtain [11C](R)-PK11195 regional binding potential values for motor and "extra-motor" regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clin. (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathol. is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways.436Paganoni, S.; Alshikho, M. J.; Luppino, S.; Chan, J.; Pothier, L.; Schoenfeld, D.; Andres, P. L.; Babu, S.; Zürcher, N. R.; Loggia, M. L.; Barry, R. L.; Luotti, S.; Nardo, G.; Trolese, M. C.; Pantalone, S.; Bendotti, C.; Bonetto, V.; De Marchi, F.; Rosen, B.; Hooker, J.; Cudkowicz, M.; Atassi, N. A pilot trial of RNS60 in amyotrophic lateral sclerosis. Muscle Nerve 2019, 59, 303– 308, DOI: 10.1002/mus.26385[Crossref], [PubMed], [CAS], Google Scholar436https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtVOmsLY%253D&md5=93f8c116b3c40a6b36190ad48b6aaca9A pilot trial of RNS60 in amyotrophic lateral sclerosisPaganoni, Sabrina; Alshikho, Mohamad J.; Luppino, Sarah; Chan, James; Pothier, Lindsay; Schoenfeld, David; Andres, Patricia L.; Babu, Suma; Zuercher, Nicole R.; Loggia, Marco L.; Barry, Robert L.; Luotti, Silvia; Nardo, Giovanni; Trolese, Maria Chiara; Pantalone, Serena; Bendotti, Caterina; Bonetto, Valentina; De Marchi, Fabiola; Rosen, Bruce; Hooker, Jacob; Cudkowicz, Merit; Atassi, NazemMuscle & Nerve (2019), 59 (3), 303-308CODEN: MUNEDE; ISSN:0148-639X. (John Wiley & Sons, Inc.)RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclin. models. RNS60 is administered by weekly i.v. infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients. The planned treatment duration was 23 wk and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomog. (PET) imaging and plasma biomarkers of inflammation. Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 wk of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers. Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression.437Liang, S. H.; Chen, J. M.; Normandin, M. D.; Chang, J. S.; Chang, G. C.; Taylor, C. K.; Trapa, P.; Plummer, M. S.; Para, K. S.; Conn, E. L.; Lopresti-Morrow, L.; Lanyon, L. F.; Cook, J. M.; Richter, K. E. G.; Nolan, C. E.; Schachter, J. B.; Janat, F.; Che, Y.; Shanmugasundaram, V.; Lefker, B. A.; Enerson, B. E.; Livni, E.; Wang, L.; Guehl, N. J.; Patnaik, D.; Wagner, F. F.; Perlis, R.; Holson, E. B.; Haggarty, S. J.; El Fakhri, G.; Kurumbail, R. G.; Vasdev, N. Discovery of a highly selective glycogen synthase kinase-3 inhibitor (PF-04802367) that modulates tau phosphorylation in the brain: Translation for PET neuroimaging. Angew. Chem., Int. Ed. 2016, 55, 9601– 9605, DOI: 10.1002/anie.201603797[Crossref], [PubMed], [CAS], Google Scholar437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtV2itLbF&md5=83a1bfbe16022e6cc30445c2afbab0a1Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET NeuroimagingLiang, Steven H.; Chen, Jinshan Michael; Normandin, Marc D.; Chang, Jeanne S.; Chang, George C.; Taylor, Christine K.; Trapa, Patrick; Plummer, Mark S.; Para, Kimberly S.; Conn, Edward L.; Lopresti-Morrow, Lori; Lanyon, Lorraine F.; Cook, James M.; Richter, Karl E. G.; Nolan, Charlie E.; Schachter, Joel B.; Janat, Fouad; Che, Ye; Shanmugasundaram, Veerabahu; Lefker, Bruce A.; Enerson, Bradley E.; Livni, Elijahu; Wang, Lu; Guehl, Nicolas J.; Patnaik, Debasis; Wagner, Florence F.; Perlis, Roy; Holson, Edward B.; Haggarty, Stephen J.; El Fakhri, Georges; Kurumbail, Ravi G.; Vasdev, NeilAngewandte Chemie, International Edition (2016), 55 (33), 9601-9605CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncol., and neurol. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A 11C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.438Benito, C.; Tolón, R. M.; Pazos, M. R.; Núñez, E.; Castillo, A. I.; Romero, J. Cannabinoid CB2 receptors in human brain inflammation. Br. J. Pharmacol. 2008, 153, 277– 285, DOI: 10.1038/sj.bjp.0707505[Crossref], [PubMed], [CAS], Google Scholar438https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovFCktg%253D%253D&md5=acc7f2244e1db16d66e5953eadecb381Cannabinoid CB2 receptors in human brain inflammationBenito, C.; Tolon, R. M.; Pazos, M. R.; Nunez, E.; Castillo, A. I.; Romero, J.British Journal of Pharmacology (2008), 153 (2), 277-285CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)A review. The presence of functional cannabinoid CB2 receptors in the CNS has provoked considerable controversy over the past few years. Formerly considered as an exclusively peripheral receptor, it is now accepted that it is also present in limited amts. and distinct locations in the brain of several animal species, including humans. Furthermore, the inducible nature of these receptors under neuroinflammatory conditions, in contrast to CB1, makes them attractive targets for the development of novel therapeutic approaches. In fact, the undesired psychoactive effects caused by CB1 activation have largely limited the clin. use of cannabinoid-related compds. that act on these receptors. In this review some recent findings on the antiinflammatory properties of CB2 receptors are presented, as well as new perspectives that have been obtained based on studies of human postmortem brain samples. In addn., various working hypotheses are also proposed and discussed. British Journal of Pharmacol. (2008) 153, 277-285; doi:10.1038/sj.bjp.0707505; published online 15 Oct. 2007.439Benito, C.; Núñez, E.; Tolón, R. M.; Carrier, E. J.; Rábano, A.; Hillard, C. J.; Romero, J. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J. Neurosci. 2003, 23, 11136– 11141, DOI: 10.1523/JNEUROSCI.23-35-11136.2003[Crossref], [PubMed], [CAS], Google Scholar439https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvV2gtbw%253D&md5=c324980efac10a672fc425ef376694f1Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brainsBenito, Cristina; Nunez, Estefania; Tolon, Rosa M.; Carrier, Erica J.; Rabano, Alberto; Hillard, Cecilia J.; Romero, JulianJournal of Neuroscience (2003), 23 (35), 11136-11141CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)The endocannabinoid system is still poorly understood. Recently, the basic elements that constitute it, i.e., membrane receptors, endogenous ligands, and mechanisms for termination of the signaling process, have been partially characterized. There is a considerable lack of information, however, concerning the distribution, concn., and function of those components in the human body, particularly during pathol. events. We have studied the status of some of the components of the endocannabinoid system, fatty acid amide hydrolase and cannabinoid CB1 and CB2 receptors, in postmortem brains from patients with Alzheimer's disease. Using specific polyclonal antibodies, we have performed immunohistochem. anal. in hippocampus and entorhinal cortex sections from brains of Alzheimer's disease patients. Our results show that both fatty acid amide hydrolase and cannabinoid CB2 receptors are abundantly and selectively expressed in neuritic plaque-assocd. astrocytes and microglia, resp., whereas the expression of CB1 receptors remains unchanged. In addn., the hydrolase activity seems to be elevated in the plaques and surrounding areas. Thus, some elements of the endocannabinoid system may be postulated as possible modulators of the inflammatory response assocd. with this neurodegenerative process and as possible targets for new therapeutic approaches.440Ahamed, M.; van Veghel, D.; Ullmer, C.; Van Laere, K.; Verbruggen, A.; Bormans, G. M. Synthesis, biodistribution and in vitro evaluation of brain permeable high affinity type 2 cannabinoid receptor agonists [11C]MA2 and [18F]MA3. Front. Neurosci. 2016, 10, 431, DOI: 10.3389/fnins.2016.00431[Crossref], [PubMed], [CAS], Google Scholar440https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svnvFKktg%253D%253D&md5=3240509303d6d5aa35daa26c7e8a59fbSynthesis, Biodistribution and In vitro Evaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [(11)C]MA2 and [(18)F]MA3Ahamed Muneer; van Veghel Daisy; Verbruggen Alfons; Bormans Guy M; Ullmer Christoph; Van Laere KoenFrontiers in neuroscience (2016), 10 (), 431 ISSN:1662-4548.The type 2 cannabinoid receptor (CB2) is a member of the endocannabinoid system and is known for its important role in (neuro)inflammation. A PET-imaging agent that allows in vivo visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and in vitro evaluation of a carbon-11 ([(11)C]MA2) and a fluorine-18 ([(18)F]MA3) labeled analog of a highly potent N-arylamide oxadiazole CB2 agonist (EC50 = 0.015 nM). MA2 and MA3 behaved as potent CB2 agonist (EC50: 3 nM and 0.1 nM, respectively) and their in vitro binding affinity for hCB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group) was found to have higher binding affinity and EC50 values when compared to the originally reported trifluoromethyl analog 12. [(11)C]MA2 and [(18)F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [(11)C]MA2 and [(18)F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes for in vivo imaging of brain CB2 receptors. However, in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted.441Haider, A.; Spinelli, F.; Herde, A. M.; Mu, B.; Keller, C.; Margelisch, M.; Weber, M.; Schibli, R.; Mu, L.; Ametamey, S. M. Evaluation of 4-oxo-quinoline-based CB2 PET radioligands in R6/2 chorea Huntington mouse model and human ALS spinal cord tissue. Eur. J. Med. Chem. 2018, 145, 746– 759, DOI: 10.1016/j.ejmech.2017.12.097[Crossref], [PubMed], [CAS], Google Scholar441https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlOhsL0%253D&md5=12d0514c79a7a3e45b1aa751971af494Evaluation of 4-oxo-quinoline-based CB2 PET radioligands in R6/2 chorea huntington mouse model and human ALS spinal cord tissueHaider, Ahmed; Spinelli, Francesco; Herde, Adrienne Muller; Mu, Boshuai; Keller, Claudia; Margelisch, Markus; Weber, Markus; Schibli, Roger; Mu, Linjing; Ametamey, Simon M.European Journal of Medicinal Chemistry (2018), 145 (), 746-759CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)The cannabinoid receptor 2 (CB2) has been implicated in a series of neurodegenerative disorders and has emerged as an interesting biol. target for therapeutic as well as diagnostic purposes. In the present work, we describe an improved radiosynthetic approach to obtain the previously reported CB2-specific PET radioligand [18F]RS-126 in higher radiochem. yields and molar activities. Addnl., the study revealed that prolongation of the [18F]RS-126 fluoroalkyl side chain ultimately leads to an improved stability towards mouse liver enzymes but is accompanied by a redn. in selectivity over the cannabinoid receptor 1 (CB1). Huntington-related phenotypic changes as well as striatal D2R downregulation were confirmed for the transgenic R6/2 mouse model. CB2 upregulation in R6/2 Chorea Huntington mice was obsd. in hippocampus, cortex, striatum and cerebellum by qPCR, however, these results could not be confirmed at the protein level by PET imaging. Furthermore, we evaluated the utility of the newly developed [11C]RS-028, a potent [18F]RS-126 deriv. with increased polarity and high selectivity over CB1 in post-mortem human ALS spinal cord and control tissue. Applying in vitro autoradiog., the translational relevance of CB2 imaging was demonstrated by the specific binding of [11C]RS-028 to post-mortem human ALS spinal cord tissue.442Mu, L.; Bieri, D.; Slavik, R.; Drandarov, K.; Müller, A.; Cermak, S.; Weber, M.; Schibli, R.; Krämer, S. D.; Ametamey, S. M. Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor. J. Neurochem. 2013, 126, 616– 624, DOI: 10.1111/jnc.12354[Crossref], [PubMed], [CAS], Google Scholar442https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlSqu7zN&md5=863e2ab5064c38648f1618a9a2424410Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptorMu, Linjing; Bieri, Daniel; Slavik, Roger; Drandarov, Konstantin; Mueller, Adrienne; Cermak, Stjepko; Weber, Markus; Schibli, Roger; Kraemer, Stefanie D.; Ametamey, Simon M.Journal of Neurochemistry (2013), 126 (5&6), 616-624CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The cannabinoid type 2 (CB2) receptor plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease and is therefore a very promising target for therapeutic approaches as well as for imaging. Based on the literature, we identified one 4-oxoquinoline deriv. (designated KD2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB2. [11C]KD2 was obtained in 99% radiochem. purity. Moderate blood-brain barrier (BBB) passage was predicted for KD2 from an in vitro transport assay with P-glycoprotein-transfected Madin Darby canine kidney cells. No efflux of KD2 by P-glycoprotein was detected. In vitro autoradiog. of rat and mouse spleen slices demonstrated that [11C]KD2 exhibits high specific binding towards CB2. High spleen uptake of [11C]KD2 was obsd. in dynamic positron emission tomog. (PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB2 agonist, GW405833. A pilot autoradiog. study with post-mortem spinal cord slices from amyotrophic lateral sclerosis (ALS) patients with [11C]KD2 suggested the presence of CB2 receptors under disease conditions. Specificity of [11C]KD2 binding could also be demonstrated on these human tissues. In conclusion, [11C]KD2 shows good in vitro and in vivo properties as a potential PET tracer for CB2. The cannabinoid type 2 receptor (CB2) plays an important role in neuroinflammatory and neuro-degenerative diseases. [11C]KD2, a new CB2 radioligand, exhibits selectivity towards CB2 receptor in vitro and in vivo in rat. A pilot autoradiog. study with spinal cord slices from amyotrophic lateral sclerosis patients with [11C]KD2 suggested the presence of CB2 under disease conditions (Figure). Selective CB2 agonist, GW405833.443Puchałowicz, K.; Tarnowski, M.; Baranowska-Bosiacka, I.; Chlubek, D.; Dziedziejko, V. P2X and P2Y receptors—Role in the pathophysiology of the nervous system. Int. J. Mol. Sci. 2014, 15, 23672– 23704, DOI: 10.3390/ijms151223672[Crossref], [PubMed], [CAS], Google Scholar443https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsl2jug%253D%253D&md5=c6aa1b669c9167f2bacd16e99f995304P2X and P2Y receptors-role in the pathophysiology of the nervous systemPuchalowicz, Kamila; Tarnowski, Maciej; Baranowska-Bosiacka, Irena; Chlubek, Dariusz; Dziedziejko, ViolettaInternational Journal of Molecular Sciences (2014), 15 (12), 23672-23704, 33 pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Purinergic signalling plays a crucial role in proper functioning of the nervous system. Mechanisms depending on extracellular nucleotides and their P2 receptors also underlie a no. of nervous system dysfunctions. This review aims to present the role of purinergic signalling, with particular focus devoted to role of P2 family receptors, in epilepsy, depression, neuropathic pain, nervous system neoplasms, such as glioma and neuroblastoma, neurodegenerative diseases like Parkinson's disease, Alzheimer's disease and multiple sclerosis. The above-mentioned conditions are assocd. with changes in expression of extracellular ectonucleotidases, P2X and P2Y receptors in neurons and glial cells, as well as releasing considerable amts. of nucleotides from activated or damaged nervous tissue cells into the extracellular space, which contributes to disturbance in purinergic signalling. The numerous studies indicate a potential possibility of using synthetic agonists/antagonists of P2 receptors in treatment of selected nervous system diseases. This is of particular significance, since numerous available agents reveal a low effectiveness and often produce side effects.444Janssen, B.; Vugts, D. J.; Funke, U.; Spaans, A.; Schuit, R. C.; Kooijman, E.; Rongen, M.; Perk, L. R.; Lammertsma, A. A.; Windhorst, A. D. Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A-740003 as a novel tracer of neuroinflammation: Synthesis and initial preclinical evaluation of [11C]A-740003. J. Labelled Compd. Radiopharm. 2014, 57, 509– 516, DOI: 10.1002/jlcr.3206[Crossref], [PubMed], [CAS], Google Scholar444https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtV2ju7vI&md5=984ecb5c357bc4297576edb73a7d6b28Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A-740003 as a novel tracer of neuroinflammationJanssen, Bieneke; Vugts, Danielle J.; Funke, Uta; Spaans, Arnold; Schuit, Robert C.; Kooijman, Esther; Rongen, Marissa; Perk, Lars R.; Lammertsma, Adriaan A.; Windhorst, Albert D.Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (8), 509-516CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)Neuroinflammation, in particular activation of microglia, is thought to play an important role in the progression of neurodegenerative diseases. In activated microglia, the purinergic P2X7 receptor is upregulated. A-740003, a highly affine and selective P2X7 receptor antagonist, is a promising candidate for the development of a radiotracer for imaging of neuroinflammation by positron emission tomog. For this purpose, [11C]A-740003 was synthesized and evaluated in vivo with respect to both tracer metab. and biodistribution. In plasma, a moderate metabolic rate was seen. In healthy rat brain, only marginal uptake of [11C]A-740003 was obsd. and, therefore, metabolites in brain could not be detd. Whether the minimal brain uptake is due to the low expression levels of the P2X7 receptor in healthy brain or to limited transport across the blood-brain barrier has yet to be elucidated.445Ory, D.; Celen, S.; Gijsbers, R.; Van Den Haute, C.; Postnov, A.; Koole, M.; Vandeputte, C.; Andres, J.-I.; Alcazar, J.; De Angelis, M.; Langlois, X.; Bhattacharya, A.; Schmidt, M.; Letavic, M. A.; Vanduffel, W.; Van Laere, K.; Verbruggen, A.; Debyser, Z.; Bormans, G. Preclinical evaluation of a P2 × 7 receptor-selective radiotracer: PET studies in a rat model with local overexpression of the human P2 × 7 receptor and in nonhuman primates. J. Nucl. Med. 2016, 57, 1436– 1441, DOI: 10.2967/jnumed.115.169995[Crossref], [PubMed], [CAS], Google Scholar445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslaktLbF&md5=16eff3aaba96236308c909eaa79f154cPreclinical evaluation of a P2X7 receptor-selective radiotracer: PET studies in a rat model with local overexpression of the human P2X7 receptor and in nonhuman primatesOry, Dieter; Celen, Sofie; Gijsbers, Rik; Van Den Haute, Chris; Postnov, Andrey; Koole, Michel; Vandeputte, Caroline; Andres, Jose-Ignacio; Alcazar, Jesus; De Angelis, Meri; Langlois, Xavier; Bhattacharya, Anindya; Schmidt, Mark; Letavic, Michael A.; Vanduffel, Wim; Van Laere, Koen; Verbruggen, Alfons; Debyser, Zeger; Bormans, GuyJournal of Nuclear Medicine (2016), 57 (9), 1436-1441CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)The P2X7 receptor (P2X7R) orchestrates neuroinflammation, and this is the basis for an increased interest in the development of antagonists inhibiting P2X7R function in the brain. This study provides the preclin. evaluation of 11C-JNJ-54173717, a PET tracer for P2X7R in both rats and nonhuman primates. 11C-JNJ-54173717 is a high-affinity radiotracer for the human P2X7R (hP2X7R). Biodistribution and radiometabolite studies were performed. Viral vectors encoding either enhanced green fluorescent protein-hP2X7R or 3flag-hP2X7R were engineered and validated in cell culture. HP2X7R was regionally overexpressed in the rat striatum after stereotactic injection of viral vectors. Dynamic small-animal PET studies were performed in vector-injected rats and in healthy monkeys using 11C-JNJ-54173717. The affinity of JNJ-54173717 was 1.6 ± 0.1 nM in a rat cortex P2X7R membrane binding assay. In a functional assay at the recombinant human and rat P2X7R orthologs, the half maximal inhibitory concn. (IC50) of JNJ-54173717 was 4.2 ± 0.01 nM and 7.6 ± 0.01 nM, resp. The rat biodistribution study showed that 11C-JNJ-54173717 crossed the blood-brain barrier and was cleared from plasma mainly via the hepatobiliary pathway. A polar radiometabolite was found in rat plasma. No radiometabolites were detected in rat brain. Dynamic small-animal PET showed binding of 11C-JNJ-54173717 in the striatum expressing hP2X7R, with rapid washout from the noninjected control striatum and other brain regions. Likewise, 11C-JNJ-54173717 PET signal was blocked by a chem. distinct P2X7R ligand, indicating specific binding to P2X7R in the monkey brain. JNJ-54173717 is a high-affinity P2X7R antagonist. An animal rat model stably expressing hP2X7R was developed and validated, identifying favorable characteristics for 11C-JNJ-54173717 as a PET radioligand for in vivo visualization of hP2X7R. 11C-JNJ-54173717 selectively visualized P2X7R in the monkey brain, and this radioligand will be further evaluated in a clin. setting to study P2X7R expression levels in neurodegenerative disorders.446Janssen, B.; Vugts, D. J.; Molenaar, G. T. Synthesis og the first carbon-11 labelled P2Y12 receptor antagonist for imaging the anti-inflammatory phenotype of activated microglia. In 18th European Symposium on Radiopharmacy and Radiopharmaceuticals. Salzburg, Austria, EJNMMI Radiopharmacy and Chemistry; 2016; Vol. 1, p 10.447Van Weehaeghe, D.; Van Schoor, E.; De Vocht, J.; Koole, M.; Attili, B.; Celen, S.; Declercq, L.; Thal, D. R.; Van Damme, P.; Bormans, G.; Van Laere, K. TSPO versus P2 × 7 as a target for neuroinflammation: An in vitro and in vivo study. J. Nucl. Med. 2020, 61, 604– 607, DOI: 10.2967/jnumed.119.231985[Crossref], [PubMed], [CAS], Google Scholar447https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVOisLbE&md5=a35e3546525ae8e8e5115a385f1de054TSPO Versus P2X7 as a target for neuroinflammation: an in vitro and in vivo studyVan Weehaeghe, Donatienne; Van Schoor, Evelien; De Vocht, Joke; Koole, Michel; Attili, Bala; Celen, Sofie; Declercq, Lieven; Thal, Dietmar R.; Van Damme, Philip; Bormans, Guy; Van Laere, KoenJournal of Nuclear Medicine (2020), 61 (4), 604-607CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Neuroinflammation is important in amyotrophic lateral sclerosis (ALS). The P2X7 receptor (P2X7R) is a promising target for neuroinflammation. The objective of this study was to compare 18F-DPA714, a second-generation translocator protein tracer, with 11C-JNJ717, a novel P2X7R tracer, in vitro and in vivo in ALS. For the in vitro portion of the study, autoradiog. with 18F-DPA714 and 11C-JNJ717 was performed on human ALS brain sections in comparison to immunofluorescence with Iba1 and GFAP. For the in vivo portion, 3 male patients with early-stage ALS (59.3 ± 7.2 y old) and 6 healthy volunteers (48.2 ± 16.5 y old, 2 men and 4 women) underwent dynamic PET/MR scanning with 18F-DPA714 and 11C-JNJ717. Vol.-of-distribution images were calcd. using Logan plots and analyzed on a vol.-of-interest basis. Autoradiog. showed no difference in 11C-JNJ717 binding but did show increased 18F-DPA714 binding in the motor cortex correlating with Iba1 expression (glial cells). Similar findings were obsd. in vivo, with a 13% increase in 18F-DPA714 binding in the motor cortex. Conclusion: In symptomatic ALS patients, 18F-DPA714 showed increased signal whereas 11C-JNJ717 was not elevated.448Kawamura, K.; Maeda, J.; Hatori, A.; Okauchi, T.; Nagai, Y.; Higuchi, M.; Suhara, T.; Fukumura, T.; Zhang, M.-R. In vivo and in vitro imaging of I2 imidazoline receptors in the monkey brain. Synapse 2011, 65, 452– 455, DOI: 10.1002/syn.20897[Crossref], [PubMed], [CAS], Google Scholar448https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisF2hsbY%253D&md5=5c08dcfcc21875edc8c799cf584ff4d7In vivo and in vitro imaging of I2 imidazoline receptors in the monkey brainKawamura, Kazunori; Maeda, Jun; Hatori, Akiko; Okauchi, Takashi; Nagai, Yuji; Higuchi, Makoto; Suhara, Tetsuya; Fukumura, Toshimitsu; Zhang, Ming-RongSynapse (Hoboken, NJ, United States) (2011), 65 (5), 452-455CODEN: SYNAET; ISSN:0887-4476. (Wiley-Liss, Inc.)I2 imidazoline receptors (I2Rs) are assocd. with depression, Alzheimer's disease, and Huntington's disease. However, in vivo imaging of I2Rs in the monkey brain has not been reported until now. We performed in vitro and in vivo imaging of (I2Rs) in the monkey brain using 11C-labeled 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD) which has high and selective affinity of I2Rs. In an auto-radiog. (ARG) study, the distribution pattern of [11C]FTIMD in the monkey brain was similar to that of [3H]idazoxan binging to I2Rs in the human brain, which was previously described. The specific binding of [11C]FTIMD accounted for >97% of total binding in brain regions existing I2Rs. In positron emission tomog. (PET) studies, the radioactivity was accumulated in brain regions existing I2Rs ligand BU224, the accumulated radioactivity was decreased to approx. 66%-75% of the baseline measurement at 15-45 min after injection of [11C]FTIMD. These results suggest that [11C]FTIMD shows the specific-binging to I2Rs in the monkey brain as depicted by PET and ARG. We performed the first in vivo imaging of I2Rs using [11C]FTIMD in the monkey brain. Synapse, 2011. © 2010 Wiley-Liss, Inc.449Kawamura, K.; Naganawa, M.; Konno, F.; Yui, J.; Wakizaka, H.; Yamasaki, T.; Yanamoto, K.; Hatori, A.; Takei, M.; Yoshida, Y.; Sakaguchi, K.; Fukumura, T.; Kimura, Y.; Zhang, M.-R. Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4–11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). Nucl. Med. Biol. 2010, 37, 625– 635, DOI: 10.1016/j.nucmedbio.2010.02.013[Crossref], [PubMed], [CAS], Google Scholar449https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVOqu7c%253D&md5=c75ac9cfcffcafb1803c5f7bd9e865f9Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD)Kawamura, Kazunori; Naganawa, Mika; Konno, Fujiko; Yui, Joji; Wakizaka, Hidekatsu; Yamasaki, Tomoteru; Yanamoto, Kazuhiko; Hatori, Akiko; Takei, Makoto; Yoshida, Yuichiro; Sakaguchi, Kazuya; Fukumura, Toshimitsu; Kimura, Yuichi; Zhang, Ming-RongNuclear Medicine and Biology (2010), 37 (5), 625-635CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)Introduction: Imidazoline receptors (IRs) have been established as distinct receptors, and have been categorized into at least two subtypes (I1R and I2R). I2Rs are assocd. with depression, Alzheimer's disease, Huntington's disease and Parkinson's disease. A few positron emission tomog. (PET) probes for I2Rs have been synthesized, but a selective PET probe has not been evaluated for the imaging of I2Rs by PET. We labeled a selective I2R ligand 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole (FTIMD) with 11C and performed the first imaging of I2Rs by PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). Methods: [11C]FTIMD was prepd. by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11C]methyl iodide in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri(o-tol)phosphine. Biodistribution was investigated in rats by tissue dissection. [11C]FTIMD metabolites were measured in brain tissues and plasma. Dynamic PET scans were acquired in rats, and the kinetic parameters estd. Results: [11C]FTIMD was successfully synthesized with a suitable radioactivity for the injection. Co-injection with 0.1 mg/kg of cold FTIMD and BU224 induced a significant redn. in the brain-to-blood ratio 15 and 30 min after the injection. In metabolite anal., unchanged [11C]FTIMD in the brain was high (98%) 30 min after the injection. In PET studies, high radioactivity levels were obsd. in regions with a high d. of I2R. The radioactivity levels and V T values in the brain regions were prominently reduced by 1.0 mg/kg of BU224 pretreatment as compared with control. Conclusion: [11C]FTIMD showed specific binding to I2Rs in rat brains with a high d. of I2R.450Kealey, S.; Turner, E. M.; Husbands, S. M.; Salinas, C. A.; Jakobsen, S.; Tyacke, R. J.; Nutt, D. J.; Parker, C. A.; Gee, A. D. Imaging imidazoline-I2 binding sites in porcine brain using 11C-BU99008. J. Nucl. Med. 2013, 54, 139– 144, DOI: 10.2967/jnumed.112.108258[Crossref], [PubMed], [CAS], Google Scholar450https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFGjtLk%253D&md5=68e67a8c76efead745862846b6fe3037Imaging imidazoline-I2 binding sites in porcine brain using 11C-BU99008Kealey, Steven; Turner, Emma M.; Husbands, Stephen M.; Salinas, Cristian A.; Jakobsen, Steen; Tyacke, Robin J.; Nutt, David J.; Parker, Christine A.; Gee, Antony D.Journal of Nuclear Medicine (2013), 54 (1), 139-144CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)Changes in the d. of imidazofine-I2 binding sites have been obsd. in a range of neurol. disorders including Alzheimer's disease, Huntington's chorea, and glial tumor; however, the precise function of these sites remains unclear. A PET probe for I2 binding sites would further our understanding of the target and may find application as a biomarker for early disease diagnosis. Compd. BU99008 has previously been identified as a promising I2 ligand from autoradiog. studies, displaying high affinity and good selectivity toward the target. In this study, BU99008 was radiolabeled with 11C in order to image the I2 binding sites in vivo using PET. Methods: 11C-BU99008 was radiolabeled by N-alkylation of the desmethyl precursor using 11C-Me iodide. A series of PET expts. was performed to investigate the binding of 11C-BU99008 in porcine brains, in the presence or absence of a nonradiolabeled, competing I2 ligand, BU224. Results: 11C-BU99008 was obtained in good yield and specific activity. In vivo, 11C-BU99008 displayed good brain penetration and gave a heterogeneous distribution with high uptake in the thalamus and low uptake in the cortex and cerebellum. 11C-BU99008 brain kinetics were well described by the 1-tissue-compartment model, which was used to provide ests. for the total vol. of distribution (VT) across brain regions of interest. Baseline VT values were ranked in the following order: thalamus > striatum > hippocampus > frontal cortex ≥ cerebellum, consistent with the known distribution and concn. of I2 binding sites. Administration of a selective I2 binding site ligand, BU224, reduced the VT to near-homogeneous levels in all brain regions. Conclusion: 11C-BU99008 appears to be a suitable PET radioligand for imaging the I2 binding sites in vivo.451Parker, C. A.; Nabulsi, N.; Holden, D.; Lin, S. -f.; Cass, T.; Labaree, D.; Kealey, S.; Gee, A. D.; Husbands, S. M.; Quelch, D.; Carson, R. E.; Nutt, D. J.; Huang, Y.; Tyacke, R. J. Evaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding sites in rhesus brain. J. Nucl. Med. 2014, 55, 838– 844, DOI: 10.2967/jnumed.113.131854[Crossref], [PubMed], [CAS], Google Scholar451https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1CrsL0%253D&md5=28a20fa3406a91bd6d8d63edea29106aEvaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding sites in rhesus brainParker, Christine A.; Nabulsi, Nabeel; Holden, Daniel; Lin, Shu-fei; Cass, Tara; Labaree, David; Kealey, Steven; Gee, Antony D.; Husbands, Stephen M.; Quelch, Darren; Carson, Richard E.; Nutt, David J.; Huang, Yiyun; Tyacke, Robin J.Journal of Nuclear Medicine (2014), 55 (5), 838-844CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)The development of a PET radioligand selective for I2-imidazoline binding sites (I2BS) would enable, for the first time, specific, measurable in vivo imaging of this target protein, along with assessment of alterations in expression patterns of this protein in disease pathophysiol. Methods: BU99008 was identified as the most promising I2BS radioligand candidate and radiolabeled with 11C via methylation. The in vivo binding properties of 11C-BU99008 were assessed in rhesus monkeys to det. brain penetration, brain distribution, binding specificity and selectivity (via the use of the unlabeled blockers), and the most appropriate kinetic mode) for analyzing data generated with this PET radioligand. Results: 11C-BU99008 was demonstrated to readily enter the brain, resulting in a heterogeneous distribution (globus pallidus > cortical regions > cerebellum) consistent with the reported regional I2BS densities as detd. by human tissue section autoradiog. and preclin. in vivo PET studies in the pig. In vivo competition studies revealed that 11C-BU99008 displayed reversible kinetics specific for the I2BS. The multilinear anal. (MA1) model was the most appropriate anal. method for this PET radioligand in this species. The selective I2BS blocker BU224 was shown to cause a saturable, dose-dependent decrease in 11C-BU99008 binding in all regions of the brain assessed, further demonstrating the heterogeneous distribution of I2BS protein in the rhesus brain and binding specificity for this radioligand. Conclusion: These data demonstrate that 11C-BU99008 represents a specific and selective PET radioligand for imaging and quantifying the I2BS, in vivo, in the rhesus monkey. Further work is under way to translate the use of 11C-BU99008 to the clinic.452Tyacke, R. J.; Myers, J. F. M.; Venkataraman, A.; Mick, I.; Turton, S.; Passchier, J.; Husbands, S. M.; Rabiner, E. A.; Gunn, R. N.; Murphy, P. S.; Parker, C. A.; Nutt, D. J. Evaluation of 11 C-BU99008, a PET ligand for the imidazoline2 binding site in human brain. J. Nucl. Med. 2018, 59, 1597– 1602, DOI: 10.2967/jnumed.118.208009[Crossref], [PubMed], [CAS], Google Scholar452https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXktVajtrY%253D&md5=49ef228fd095cac95ce9d8edc1d10339Evaluation of 11C-BU99008, a PET ligand for the Imidazoline2 binding site in human brainTyacke, Robin J.; Myers, Jim F. M.; Venkataraman, Ashwin; Mick, Inge; Turton, Samuel; Passchier, Jan; Husbands, Stephen M.; Rabiner, Eugenii A.; Gunn, Roger N.; Murphy, Philip S.; Parker, Christine A.; Nutt, David J.Journal of Nuclear Medicine (2018), 59 (10), 1597-1602CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)The imidazoline2 binding site (I2BS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C-BU99008 has previously been identified as a putative PET radioligand. Here, we present the first in vivo characterization of this PET radioligand in humans and assess its test-retest reproducibility. Methods: Fourteen healthy male volunteers underwent dynamic PET imaging with 11C-BU99008 and arterial sampling. Six subjects were used in a test-retest assessment, and 8 were used in a pharmacol. evaluation, undergoing a second or third heterologous competition scan with the mixed I2BS/α2-adrenoceptor drug idazoxan (n = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid (n = 4; 50 mg). Regional time-activity data were generated from arterial plasma input functions cor. for metabolites using the most appropriate model to derive the outcome measure VT (regional distribution vol.). All image processing and kinetic analyses were performed in MIAKAT. Results: Brain uptake of 11C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment model was preferred. VT ests. were high in the striatum (105 ± 21 mL·cm-3), medium in the cingulate cortex (62 ± 10 mL·cm-3), and low in the cerebellum (41 ± 7 mL·cm-3). Test-retest reliability was reasonable. The uptake was dose-dependently reduced throughout the brain by pretreatment with idazoxan, with an av. block across all regions of about 60% (VT, ∼30 mL·cm-3) at the highest dose (80 mg). The median ED for idazoxan was 28 mg. Uptake was not blocked by pretreatment with the monoamine oxidase inhibitor isocarboxazid. Conclusion: 11C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I2BS distribution, and good test-retest reliability.453Ekblom, J.; Jossan, S. S.; Oreland, L.; Walum, E.; Aquilonius, S.-M. Reactive Gliosis and Monoamine Oxidase B. In Amine Oxidases: Function and Dysfunction; Tipton, K. F., Youdim, M. B. H., Barwell, C. J., Callingham, B. A., Lyles, G. A., Eds.; Springer: Vienna, Austria, 1994; pp 253– 258.454Schöll, M.; Carter, S. F.; Westman, E.; Rodriguez-Vieitez, E.; Almkvist, O.; Thordardottir, S.; Wall, A.; Graff, C.; Långström, B.; Nordberg, A. Early astrocytosis in autosomal dominant Alzheimer’s disease measured in vivo by multi-tracer positron emission tomography. Sci. Rep. 2015, 5, 16404, DOI: 10.1038/srep16404[Crossref], [PubMed], [CAS], Google Scholar454https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vgslCiug%253D%253D&md5=a61729478e88053544d07d38c2769f23Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomographyScholl Michael; Carter Stephen F; Rodriguez-Vieitez Elena; Almkvist Ove; Nordberg Agneta; Scholl Michael; Carter Stephen F; Westman Eric; Almkvist Ove; Thordardottir Steinunn; Graff Caroline; Nordberg Agneta; Almkvist Ove; Thordardottir Steinunn; Graff Caroline; Wall Anders; Langstrom BengtScientific reports (2015), 5 (), 16404 ISSN:.Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround β-amyloid (Aβ) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar Aβ, astrocytosis and cerebral glucose metabolism with the radiotracers (11)C-Pittsburgh compound-B (PIB), (11)C-deuterium-L-deprenyl (DED) and (18)F-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar Aβ or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.455Johansson, A.; Engler, H.; Blomquist, G.; Scott, B.; Wall, A.; Aquilonius, S.-M.; Långström, B.; Askmark, H. Evidence for astrocytosis in ALS demonstrated by [11C](l)-deprenyl-D2 PET. J. Neurol. Sci. 2007, 255, 17– 22, DOI: 10.1016/j.jns.2007.01.057[Crossref], [PubMed], [CAS], Google Scholar455https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVCjsrs%253D&md5=f9a033414237a4f0fe28eeed94557a04Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PETJohansson, Anders; Engler, Henry; Blomquist, Gunnar; Scott, Berit; Wall, Anders; Aquilonius, Sten-Magnus; Langstroem, Bengt; Askmark, HakanJournal of the Neurological Sciences (2007), 255 (1-2), 17-22CODEN: JNSCAG; ISSN:0022-510X. (Elsevier B.V.)To use deuterium-substituted [11C](L)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). In human brain, the enzyme MAO-B is primarily located in astrocytes. L-deprenyl binds to MAO-B and autoradiog. with 3H-L-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](L)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. Deuterium-substituted [11C](L)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. Increased uptake rate of [11C](L)-deprenyl was demonstrated in ALS in pons and white matter. This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](L)-deprenyl PET though further studies are needed to det. whether deuterium-substituted [11C](L)-deprenyl binding tracks disease progression and reflects astrocytosis.456Saura, J.; Bleuel, Z.; Ulrich, J.; Mendelowitsch, A.; Chen, K.; Shih, J. C.; Malherbe, P.; Da Prada, M.; Richards, J. G. Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistry. Neuroscience 1996, 70, 755– 774, DOI: 10.1016/S0306-4522(96)83013-2[Crossref], [PubMed], [CAS], Google Scholar456https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XivVKqsA%253D%253D&md5=b3a387bf13c2c99466a6ff85bdfa6993Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistrySaura, J.; Bleuel, Z.; Ulrich, J.; Mendelowitsch, A.; Chen, K.; Shih, J. C.; Malherbe, P.; Da Prada, M.; Richards, J. G.Neuroscience (Oxford) (1996), 70 (3), 755-74CODEN: NRSCDN; ISSN:0306-4522. (Elsevier)Monoamine oxidases (MAOs) are key enzymes in the metab. of amine neurotransmitters and neuromodulators and are targets for drug therapy in depression and Parkinson's and Alzheimer's diseases. Knowledge of their distribution in the brain is essential to understand their physiol. role. To study the regional distribution and abundance of MOA A and B in human brain, pituitary, and superior cervical ganglion, the authors used quant. enzyme radioautog. with radioligands, [3H]Ro41-1049 and [3H]lazabemide, resp. Furthermore, 35S-labeled oligonucleotides complementary to isoenzyme A and B mRNAs were used to map the cellular location of the resp. transcripts in adjacent sections by in situ hybridization histochem. A markedly different pattern of distribution of the isoenzymes was obsd. The highest levels of MAO A were measured in the superior cervical ganglion, locus coeruleus, interpeduncular nucleus, and ventromedial hypothalamic nucleus. The corresponding mRNA was detected only in the noradrenergic neurons of the superior cervical ganglion and locus coeruleus. In contrast to rat brain, MAO B was much more abundant in most human brain regions investigated. The highest levels were measured in the ependyma of ventricles, stria terminalis, and in individual hypothalamic neurons. MAO B transcripts were detected in serotoninergic raphe neurons, histaminergic hypothalamic neurons, and in dentate gyrus granule cells of the hippocampal formation. It was concluded that [3H]Ro41-1049 and [3H]lazabemide are extremely useful radioligands for high-resoln. analyses of the abundance and distribution of catalytic sites of MAO A and B, resp., in human brain sections. From the levels of mRNA detected, the cellular sites of synthesis of the isoenzymes are the noradrenergic neurons of the locus coeruleus (for MAO A) and the serotoninergic and histaminergic neurons of the raphe and posterior hypothalamus, resp. (for MAO B). The combination of quant. enzyme radioautog. with in situ hybridization histochem. is a useful approach to study, with high resoln., both the physiol. and pathophysiol. of MAOs in human brain.457Shukuri, M.; Takashima-Hirano, M.; Tokuda, K.; Takashima, T.; Matsumura, K.; Inoue, O.; Doi, H.; Suzuki, M.; Watanabe, Y.; Onoe, H. In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester. J. Nucl. Med. 2011, 52, 1094– 1101, DOI: 10.2967/jnumed.110.084046[Crossref], [PubMed], [CAS], Google Scholar457https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnltFGjsQ%253D%253D&md5=6721bba55894842b0f919f4cbf035ee8In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl esterShukuri Miho; Takashima-Hirano Misato; Tokuda Keiko; Takashima Tadayuki; Matsumura Kiyoshi; Inoue Osamu; Doi Hisashi; Suzuki Masaaki; Watanabe Yasuyoshi; Onoe HirotakaJournal of nuclear medicine : official publication, Society of Nuclear Medicine (2011), 52 (7), 1094-101 ISSN:.UNLABELLED: Cyclooxygenase (COX)-1 and -2 are prostanoid-synthesizing enzymes that play important roles in the regulation of neuroinflammation and in the development of neurodegenerative disorders. However, the specific functions of these isoforms are still unclear. We recently developed (11)C-labeled ketoprofen methyl ester as a PET probe that targets the COXs for imaging neuroinflammation, though its responsible isoform is yet to be determined. In the present study, we performed ex vivo and in vivo imaging studies with (11)C-ketoprofen methyl ester and determined the contributions of the COX isoforms during the neuroinflammatory process. METHODS: To identify the COX isoform responsible for (11)C-ketoprofen methyl ester in the brain, we examined the ex vivo autoradiography of (11)C-ketoprofen methyl ester using COX-deficient mice. Time-dependent changes in accumulation of (11)C-ketoprofen methyl ester during the neuroinflammatory process were evaluated by PET in rats with hemispheric neuroinflammation induced by intrastriatal injection of lipopolysaccharide or quinolinic acid. In both rat models, cell-type specificity of COX isoform expression during neuroinflammation was identified immunohistochemically. RESULTS: Ex vivo autoradiographic analysis of COX-deficient mice revealed a significant reduction of (11)C-ketoprofen methyl ester accumulation only in COX-1-deficient mice, not COX-2-deficient mice. PET of rats after intrastriatal injection of lipopolysaccharide showed a significant increase in accumulation of (11)C-ketoprofen methyl ester in the inflamed area. This increase was evident at the early phase of 6 h, peaked at day 1, and then returned to basal levels by day 7. In addition, immunohistochemical analysis revealed that the population of activated microglia and macrophages was elevated at the early phase with COX-1 expression but not COX-2. A significant increase in (11)C-ketoprofen methyl ester accumulation was also observed at day 1 after intrastriatal injection of quinolinic acid, with increased COX-1-expressing activated microglia and macrophages. CONCLUSION: We have identified (11)C-ketoprofen methyl ester as a COX-1-selective PET probe, and using this, we have also demonstrated a time-dependent expression of COX-1 in activated microglia and macrophages during the neuroinflammatory process in the living brain. Thus, COX-1 may play a crucial role in the pathology of neuroinflammation and might be a critical target for the diagnosis and therapy of neurodegenerative disorders.458Soliman, M. L.; Ohm, J. E.; Rosenberger, T. A. Acetate reduces PGE2 release and modulates phospholipase and cyclooxygenase levels in neuroglia stimulated with lipopolysaccharide. Lipids 2013, 48, 651– 662, DOI: 10.1007/s11745-013-3799-x[Crossref], [PubMed], [CAS], Google Scholar458https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXot1Oht7g%253D&md5=e9e4e1dee790b13c2535d3a953e7bbd1Acetate Reduces PGE2 Release and Modulates Phospholipase and Cyclooxygenase Levels in Neuroglia Stimulated with LipopolysaccharideSoliman, Mahmoud L.; Ohm, Joyce E.; Rosenberger, Thad A.Lipids (2013), 48 (7), 651-662CODEN: LPDSAP; ISSN:0024-4201. (Springer)Acetate supplementation attenuates neuroglial activation, increases histone and non-histone protein acetylation, reduces pro-inflammatory cytokine expression, and increases IL-4 transcription in rat models of neuroinflammation and Lyme's neuroborreliosis. Because eicosanoid signaling is involved in neuroinflammation, the authors measured the effect acetate treatment had on phospholipase, cyclooxygenase, and prostaglandin E2 (PGE2) levels in BV-2 microglia and primary astrocytes stimulated with lipopolysaccharide (LPS). In BV-2 microglia, the authors found that LPS increased the phosphorylation-state of cytosolic phospholipase A2 (cPLA2), reduced the levels of phospholipase C (PLC) β1, and increased the levels of cyclooxygenase (Cox)-1 and -2. Acetate treatment returned PLCβ1 and Cox-1 levels to normal, attenuated the increase in Cox-2, but had no effect on cPLA2 phosphorylation. In primary astrocytes, LPS increased the phosphorylation of cPLA2 and increased the levels of Cox-1 and Cox-2. Acetate treatment in these cells reduced secretory PLA2 IIA and PLCβ1 levels as compared to LPS-treatment groups, reversed the increase in cPLA2 phosphorylation, and returned Cox-1 levels to normal. Acetate treatment reduced PGE2 release in astrocytes stimulated with LPS to control levels, but did not alter PGE2 levels in BV-2 microglia. The amt. of acetylated H3K9 bound to the promoter regions of Cox-1, Cox-2, IL-1β and NF-κB p65 genes, but not IL-4 in were increased in BV-2 microglia treated with acetate. These data suggest that acetate treatment can disrupt eicosanoid signaling in neuroglia that may, in part, be the result of altering gene expression due chromatin remodeling as a result of increasing H3K9 acetylation.459Farooqui, A. A.; Horrocks, L. A.; Farooqui, T. Modulation of inflammation in brain: A matter of fat: Neuroinflammation and fatty acids. J. Neurochem. 2007, 101, 577– 599, DOI: 10.1111/j.1471-4159.2006.04371.x[Crossref], [PubMed], [CAS], Google Scholar459https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlsV2ks78%253D&md5=879ddbb62378294c03ec0c3ad7f92b4bModulation of inflammation in brain: a matter of fatFarooqui, Akhlaq A.; Horrocks, Lloyd A.; Farooqui, TahiraJournal of Neurochemistry (2007), 101 (3), 577-599CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)A review. Neuro-inflammation is a host defense mechanism assocd. with neutralization of an insult and restoration of normal structure and function of brain. Neuro-inflammation is a hallmark of all major CNS diseases. The main mediators of neuro-inflammation are microglial cells. These cells are activated during a CNS injury. Microglial cells initiate a rapid response that involves cell migration, proliferation, release of cytokines/chemokines and trophic and/or toxic effects. Cytokines/chemokines stimulate phospholipases A2 and cyclooxygenases. This results in breakdown of membrane glycerophospholipids with the release of arachidonic acid (AA) and docosahexaenoic acid (DHA). Oxidn. of AA produces pro-inflammatory prostaglandins, leukotrienes, and thromboxanes. One of the lyso-glycerophospholipids, the other products of reactions catalyzed by phospholipase A2, is used for the synthesis of pro-inflammatory platelet-activating factor. These pro-inflammatory mediators intensify neuro-inflammation. Lipoxin, an oxidized product of AA through 5-lipoxygenase, is involved in the resoln. of inflammation and is anti-inflammatory. Docosahexaenoic acid is metabolized to resolvins and neuroprotectins. These lipid mediators inhibit the generation of prostaglandins, leukotrienes, and thromboxanes. Levels of prostaglandins, leukotrienes, and thromboxanes are markedly increased in acute neural trauma and neurodegenerative diseases. Docosahexaenoic acid and its lipid mediators prevent neuro-inflammation by inhibiting transcription factor NFκB, preventing cytokine secretion, blocking the synthesis of prostaglandins, leukotrienes, and thromboxanes, and modulating leukocyte trafficking. Depending on its timing and magnitude in brain tissue, inflammation serves multiple purposes. It is involved in the protection of uninjured neurons and removal of degenerating neuronal debris and also in assisting repair and recovery processes. The dietary ratio of AA to DHA may affect neurodegeneration assocd. with acute neural trauma and neurodegenerative diseases. The dietary intake of docosahexaenoic acid offers the possibility of counter-balancing the harmful effects of high levels of AA-derived pro-inflammatory lipid mediators.460Airas, L.; Rissanen, E.; Rinne, J. O. Imaging neuroinflammation in multiple sclerosis using TSPO-PET. Clin Transl Imaging. 2015, 3, 461– 473, DOI: 10.1007/s40336-015-0147-6[Crossref], [PubMed], [CAS], Google Scholar460https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FhtlyrsA%253D%253D&md5=0330c1407a75b8ea6958d28a547c773cImaging neuroinflammation in multiple sclerosis using TSPO-PETAiras Laura; Rissanen Eero; Rinne Juha OClinical and translational imaging (2015), 3 (), 461-473 ISSN:2281-5872.Conventional MR imaging (MRI) techniques form the cornerstone of multiple sclerosis (MS) diagnostics and clinical follow-up today. MRI is sensitive in demonstrating focal inflammatory lesions and diffuse atrophy. However, especially in progressive MS, there is increasingly widespread diffuse pathology also outside the plaques, often related to microglial activation and neurodegeneration. This cannot be detected using conventional MRI. Positron emission tomography (PET) imaging using 18-kDa translocator protein (TSPO) binding radioligands has recently shown promise as a tool to detect this diffuse pathology in vivo, and for the first time allows one to follow its development longitudinally. It is becoming evident that the more advanced the MS disease is, the more pronounced is microglial activation. PET imaging allows the detection of MS-related pathology at molecular level in vivo. It has potential to enable measurement of effects of new disease-modifying drugs aimed at reducing neurodegeneration and neuroinflammation. PET imaging could thus be included in the design of future clinical trials of progressive MS. There are still technical issues related to the quality of TSPO radioligands and post-processing methodology, and comparison of studies from different PET centres is challenging. In this review, we summarise the main evidence supporting the use of TSPO-PET as a tool to explore the diffuse inflammation in MS.461Rissanen, E.; Virta, J. R.; Paavilainen, T.; Tuisku, J.; Helin, S.; Luoto, P.; Parkkola, R.; Rinne, J. O.; Airas, L. Adenosine A2A receptors in secondary progressive multiple sclerosis: A [11C]TMSX brain PET study. J. Cereb. Blood Flow Metab. 2013, 33, 1394– 1401, DOI: 10.1038/jcbfm.2013.85[Crossref], [PubMed], [CAS], Google Scholar461https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWqsbvO&md5=0dbb6f56903273f1ce5a3286e17893ccAdenosine A2A receptors in secondary progressive multiple sclerosis: a [11C]TMSX brain PET studyRissanen, Eero; Virta, Jere R.; Paavilainen, Teemu; Tuisku, Jouni; Helin, Semi; Luoto, Pauliina; Parkkola, Riitta; Rinne, Juha O.; Airas, LauraJournal of Cerebral Blood Flow & Metabolism (2013), 33 (9), 1394-1401CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)In this study, positron emission tomog. (PET) imaging with a radioligand to adenosine A2A receptors (A2AR)-a potent regulator of inflammation-was used to gain insight into the mol. alterations in normal-appearing white matter (NAWM) and gray matter (GM) in secondary progressive multiple sclerosis (SPMS). Normal-appearing white matter and GM, despite seeming normal in conventional magnetic resonance imaging (MRI), are important loci of widespread inflammation, neuronal damage, and source of progressive disability in multiple sclerosis (MS). Dynamic PET imaging using A2AR-specific [11C]TMSX and brain MRI with diffusion tensor imaging were performed to eight SPMS patients and seven healthy controls. Distribution vols. (VT) of [11C]TMSX were analyzed from 13 regions of interest using Logan plot with arterial plasma input. The SPMS patients had significantly increased [11C]TMSX-VT in NAWM compared with controls (mean (s.d.): 0.55 (±0.08) vs. 0.45 (±0.05); P=0.036). Both the increased VT and the decreased fractional anisotropy (FA) in NAWM were assocd. with higher expanded disability status scale (EDSS) scores (P=0.030 and P=0.012, resp.), whereas the T2-lesion load of SPMS patients did not correlate with EDSS. This study shows, that A2ARs are increased in the brain of SPMS patients, and that [11C]TMSX-PET provides a novel approach to learn about central nervous system pathol. in SPMS in vivo.462Stankoff, B.; Freeman, L.; Aigrot, M.-S.; Chardain, A.; Dollé, F.; Williams, A.; Galanaud, D.; Armand, L.; Lehericy, S.; Lubetzki, C.; Zalc, B.; Bottlaender, M. Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-11C]-2-(4′-methylaminophenyl)- 6-hydroxybenzothiazole. Ann. Neurol. 2011, 69, 673– 680, DOI: 10.1002/ana.22320[Crossref], [PubMed], [CAS], Google Scholar462https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltVygtLs%253D&md5=adaa87c73a372d900c81c2f7082f1a73Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-11C]-2-(4'-methylaminophenyl)- 6-hydroxybenzothiazoleStankoff, Bruno; Freeman, Leorah; Aigrot, Marie-Stephane; Chardain, Audrey; Dolle, Frederic; Williams, Anna; Galanaud, Damien; Armand, Lucie; Lehericy, Stephane; Lubetzki, Catherine; Zalc, Bernard; Bottlaender, MichelAnnals of Neurology (2011), 69 (4), 673-680CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)Objective: Imaging of myelin tracts in vivo would greatly improve the monitoring of demyelinating diseases such as multiple sclerosis (MS). To date, no imaging technique specifically targets demyelination and remyelination. Recently, amyloid markers related to Congo red have been shown to bind to central nervous system (CNS) myelin. Here we questioned whether the thioflavine-T deriv. 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), which also binds to amyloid plaques, could serve as a myelin marker. Methods: PIB fixation to myelin was studied by fluorescence in the normal and dysmyelinating mouse brain, as well as in the postmortem brain of MS patients. Positron emission tomog. (PET) expts. were conducted using [11C]PIB in baboons and in a proof of concept clin. study in 2 MS patients. Results: Applied directly on tissue sections or after i.p. injection, PIB stained CNS myelin, and the decrease in the level of fixation paralleled the amt. of myelin loss in a dysmyelinating mutant. In normally myelinated areas of postmortem MS brain, demyelinated and remyelinated lesions were clearly distinguishable by the differential intensity of labeling obsd. with PIB. PET using i.v. injected radiolabeled [11C]PIB imaged CNS myelin in baboons and humans. In MS patients, the dynamic anal. of PET acquisitions allowed quant. assessment of demyelination. Interpretation: PIB could be used as an imaging marker to quantify myelin loss and repair in demyelinating diseases.463Baron, J.-C.; Yamauchi, H.; Fujioka, M.; Endres, M. Selective neuronal loss in ischemic stroke and cerebrovascular disease. J. Cereb. Blood Flow Metab. 2014, 34, 2– 18, DOI: 10.1038/jcbfm.2013.188[Crossref], [PubMed], [CAS], Google Scholar463https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7jtFCqsw%253D%253D&md5=685ccc761936b5b0cb4ceaeede503528Selective neuronal loss in ischemic stroke and cerebrovascular diseaseBaron Jean-Claude; Yamauchi Hiroshi; Fujioka Masayuki; Endres MatthiasJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (2014), 34 (1), 2-18 ISSN:.As a sequel of brain ischemia, selective neuronal loss (SNL)-as opposed to pannecrosis (i.e. infarction)-is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and (11)C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary 'exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences-including the impact on neurological recovery and contribution to vascular cognitive impairment-association with possible causal processes such as microglial activation, and preventability of SNL.464Pascual, B.; Prieto, E.; Arbizu, J.; Marti-Climent, J. M.; Peñuelas, I.; Quincoces, G.; Zarauza, R.; Pappatà, S.; Masdeu, J. C. Decreased carbon-11-flumazenil binding in early Alzheimer’s disease. Brain 2012, 135, 2817– 2825, DOI: 10.1093/brain/aws210[Crossref], [PubMed], [CAS], Google Scholar464https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bltlyltQ%253D%253D&md5=b8fb6d1925ce2871268f67840bb9f6feDecreased carbon-11-flumazenil binding in early Alzheimer's diseasePascual Belen; Prieto Elena; Arbizu Javier; Marti-Climent Josep M; Penuelas Ivan; Quincoces Gemma; Zarauza Rosina; Pappata Sabina; Masdeu Joseph CBrain : a journal of neurology (2012), 135 (Pt 9), 2817-25 ISSN:.Neuronal loss in Alzheimer's disease, a better correlate of cognitive impairment than amyloid deposition, is currently gauged by the degree of regional atrophy. However, functional markers, such as GABA(A) receptor density, a marker of neuronal integrity, could be more sensitive. In post-mortem hippocampus, GABA(A) messenger RNA expression is reduced even in mild cognitive impairment. We measured whole-brain GABA(A) binding potential in vivo using [(11)C]-flumazenil positron emission tomography and compared GABA(A) binding with metabolic and volumetric measurements. For this purpose, we studied 12 subjects, six patients with early Alzheimer's disease and six healthy controls, with [(11)C]-flumazenil and [(18)F]-fluorodeoxyglucose positron emission tomography, as well as with high-resolution magnetic resonance imaging. Data were evaluated with both voxel-based parametric methods and volume of interest methods. We found that in early Alzheimer's disease, with voxel-based analysis, [(11)C]-flumazenil binding was decreased in infero-medial temporal cortex, retrosplenial cortex and posterior perisylvian regions. Inter-group differences reached corrected significance when using an arterial input function. Metabolism measured with positron emission tomography and volumetric measurements obtained with magnetic resonance imaging showed changes in regions affected in early Alzheimer's disease, but, unlike with [(11)C]-flumazenil binding and probably due to sample size, the voxel-based findings failed to reach corrected significance in any region of the brain. With volume of interest analysis, hippocampi and posterior cingulate gyrus showed decreased [(11)C]-flumazenil binding. In addition, [(11)C]-flumazenil hippocampal binding correlated with memory performance. Remarkably, [(11)C]-flumazenil binding was decreased precisely in the regions showing the greatest degree of neuronal loss in post-mortem studies of early Alzheimer's disease. From these data, we conclude that [(11)C]-flumazenil binding could be a useful marker of neuronal loss in early Alzheimer's disease.
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